Wellcome PhD Students: Final Year Talks
Thursday 25 September
Room 249, 2nd Floor, Medical Sciences Building, Gower Street
12.30pm: Scott Curran
12.55pm: Kristina Tubby
1.20pm: Miguel Tillo
1.45pm: Alex Sinclair-Wilson
2.10pm: Elena Scarpa
A large list of supervisors and projects throughout UCL, its related teaching hospitals and specialist centres and the National Institute for Medical Research is available to students.
A short abstract for each project, together with supervisor details, is given below. There are also links where available to supervisor web sites.
|Prof Robin Ali||Institute of Ophthalmology||Stem cell therapy for retinal degeneration|
|Dr Siew-Lan Ang||NIMR||Using mouse embryonic stem cell differentiation to identify targets of Neurogenin2 gene in midbrain dopaminergic progenitors|
|Dr Buzz Baum||MRC LMCB||
Robust patterning and
morphogenesis in a living epithelium
|Dr Katherine Bowers||Dept Structural and Molecular Biology||Mechanisms of protein sorting|
|Prof Jeremy Brockes||Dept Structural and Molecular Biology||Regeneration|
|Prof Pete Coffey||Institute of Ophthalmology||The use of human embryonic stem cells for eye disease|
|Prof Andrew Copp||Institute of Child Health||Development and stem cell involvement in mammalian neural tube formation|
|Dr Nicolas Daudet||Ear Institute||Mechanisms of hair cell development and regeneration in the inner ear|
|Dr Patrizia Ferretti||Institute of Child Health||Cellular and molecular basis of neural regeneration|
|Prof Alex Gould||NIMR||
Nutrients and neural stem cells
|Prof Linda Greensmith||Institute of Neurology||The role of heat shock proteins in axonal growth and maintenance|
|Prof François Guillemot||NIMR||Transcriptional and signalling control of neural stem cell fates|
|Prof Glen Jeffery||Institute of Ophthalmology||Interactions between the neural retina and the retinal pigment epithelium|
|Profs Kristjan R Jessen and Rhona Mirsky||Dept Cell & Developmental Biology||Schwann cell plasticity and nerve regeneration|
|Dr Nicoletta Kessaris||Wolfson Institute for Biomedical Research||Interneuron development in the forebrain|
|Prof Martin Koltzenburg||
Institute of Neurology
||Development of peripheral pain signalling neurons|
|Prof Alison Lloyd||MRC LMCB||Cell growth and regeneration|
|Prof Robin Lovell-Badge||NIMR||Characterization of a SOX2 positive pituitary stem cell/progenitor population|
|Dr Juan Pedro Martinez-Barbera||Institute of Child Health||Forebrain and pituitary development in mammals|
|Prof Roberto Mayor||Dept Cell & Developmental Biology||Migration and differentiation of the neural crest stem cells|
|Dr Paola Oliveri||Genetics, Evolution and Environment||Genetic program for the specification of neuroectoderm|
|Prof John Parnavelas||Dept Cell & Developmental Biology||
Molecular mechanisms involved in cortical neuron
|Prof Franck Pichaud||MRC LMCB||
Polarity & Morphogenesis
|Dr Stephen Price||Dept Cell & Developmental Biology||Motor nucleus formation in the spinal cord and hindbrain|
|Prof Gennadij Raivich||Perinatal Brain Repair Group||Periventricular macrophages in fountains of microglia and their role in developmental cerebral white matter injury|
|Prof Antonella Riccio||MRC LMCB||Transcriptional and epigenetic mechanisms in developing neurons|
|Prof Bill Richardson||Wolfson Institute for Biomedical Research||Generation of new neurons in the adult mouse brain|
|Prof Christiana Ruhrberg||Institute of Ophthalmology||VEGF-A signalling in boundary cap stem cells at the PNS/CNS interface|
|Prof Patricia Salinas||Dept Cell & Developmental Biology||Wnt signalling in neuronal circuit assembly and stem cell renewal|
|Prof Jane Sowden||Institute of Child Health||Developing new photoreceptors for retinal repair|
|Dr Philip Stanier||Institute of Child Health||The role of Tbx22 in palatine bone induction|
|Prof Claudio Stern||Dept Cell & Developmental Biology||Early embryo development and embryonic stem cells|
|Dr Masa Tada||Dept Cell & Developmental Biology||Analysis of cellular and molecular mechanisms underlying zebrafish gastrulation|
|Prof Jean-Paul Vincent||NIMR||Uncovering the pathway that recognises misbehaving cells during development|
|Prof David Whitmore||Dept Cell & Developmental Biology||The impact of the biological clock and light on early embryonic development|
|Prof David Wilkinson||NIMR||Regulation of boundary formation and neurogenesis|
|Prof Stephen Wilson||Dept Cell & Developmental Biology||Asymmetries in neurogenesis between left and right sides of the brain|
|Dr Yoshiyuki Yamamoto||Dept Cell & Developmental Biology||Mechanisms of lens regeneration in teleost fish|
Prof Robin Ali
Hereditary retinal disease and age related macular degeneration (AMD) are major causes of visual impairment with loss of photoreceptor cells leading to blindness. We have recently discovered that transplantation of rod precursor cells at a specific stage of development results in their integration and subsequent differentiation into rod photoreceptors that form synaptic connections and improve visual function in mouse models of retinal degeneration (MacLaren et al, Nature 2006). Stem cells, with properties of self-renewal and the potential to produce large numbers of neurons in vitro, offer an ideal donor source of cells to generate photoreceptor precursors for transplantation. Stem cells isolated from the adult ciliary margin (CM) of the eye, as well as embryonic stem cells are possible sources of large numbers of rod precursor cells. The aim of this project is to determine the local cues and transcription factors that might promote optimal integration and differentiation of transplanted stem cells. We have recently developed an integrase-deficient lentiviral vector (Yanez-Munoz et al, Nature Medicine 2006) that will be used for transient delivery of genes encoding key transcription factors or growth factors. These vectors will be used to transduce retinal stem cells within the retina or transduce stem cells before transplantation into the adult mouse in order to generate functional photoreceptors and repair degenerating retinae.
Dr Siew-Lan Ang
The hallmark of Parkinson Disease is the selective degeneration of midbrain dopaminergic (mDA) neurons of the substantia pars compacta subgroup. Intense efforts are now focused on understanding the molecular mechanisms regulating differentiation of these neurons from stem cells that could be used as a source of mDA neurons for stem cell therapy of Parkinson Disease patients. Neurogenin2 is a proneural basic-helix-loop-helix transcription factor that promotes neuronal differentiation in neural stem/progenitor cells. We have previously shown that Neurogenin2 (Ngn2) is required for the differentiation of mDA neurons (Kele et al., Dev. 2006, 133, 495) using loss of function studies in mice. To determine molecular and cellular functions of Ngn2, we have identified several candidate target genes using microarray prolifing experiments of wild-type and Ngn2-/- ventral midbrain tissue. The function of these targets will be assayed for their ability to regulate the differentiation of mDA neurons from mouse embryonic stem (ES) cells. In addition, mDA progenitors generated from differentiation of ES cells will be used to perform chromatin immunoprecipitation experiments to identify direct transcriptional targets of Ngn2. Results obtained from this project will further our understanding of molecular determinants that regulate the differentiation of mDA neurons from stem cells.
Dr Buzz Baum
During the course of this project, the
use a combination of Drosophila genetics, RNAi and live
to study the development of a robust bristle pattern in
notum. Genetic tricks and laser-induced cell ablation will
be used to determine how the epithelium is able to respond
in patterning and morphogenesis.
Finally the genes involved in normal developmental patterning and the response to wounding will be identified in an RNAi screen, using a library of flies carrying hair-pin RNAs.
Dr Katherine Bowers
In my laboratory, we study mechanisms of protein sorting. Our work has three main themes and our current projects all involve at least two of these themes:
- Ion gradients across intracellular organelles and their role in protein trafficking
- The role of phosphoinositides in protein trafficking
- Protein sorting at the multivesicular body (MVB)
We use two model systems: the yeast Saccharomyces cerevisiae (budding yeast) and mammalian tissue culture cells.
Prof Jeremy Brockes
My interests are in the cellular and molecular mechanisms underlying regeneration in salamanders. A major focus is on limb regeneration, but there is also some activity on lens regeneration. We work on positional identity in limb regeneration, the dependence of regeneration on the nerve, and the role of thrombin activation in linking regeneration and tissue injury.
Prof Pete Coffey
Two major groups of diseases termed
and age-related macular degeneration are the leading cause
Loss of vision is due to progressive death of the light
cells of the eye as a result of defects in these cells
or defects in the lining cells of the eye, the pigment
cells. There is no cure at present although several have
One of these involves the transplantation of stem cells to
We are exploring this approach further with the object of
the best conditions for transplantation, identifying
might compromise transplant efficacy, finding solutions to
deleterious effects, and assessing how much visual
be expected from this approach.
Most importantly it will provide necessary background data for preparation of this approach for use in humans. Careful studies of the kind proposed here are needed if transplantation is to be transferred successfully to human patients.
Prof Andrew Copp
Neurulation, the process by which the embryo closes its
neural tube, is a critical event in establishing the central nervous system. Failure
of any aspect of neurulation leads to neural tube defects (NTDs), a group of
severe congenital malformations that are either lethal or cause severe handicap
in childhood. Our research uses mouse mutants which develop NTDs, in order to
provide model systems for experimental analysis of normal and abnormal
neurulation. We are also extending several aspects of the mouse-based research
to humans, in order to improve our understanding of the clinical conditions and
develop novel preventive therapies. Various projects on neurulation and NTDs
are available in different aspects of this topic. For example, current
1. Live confocal-based imaging of neural tube closure in mouse embryos combining analysis of the normal process and comparison with mutants which fail in closure;
2. Defining and measuring the biomechanical properties of the closing neural tube and determining how neural tube closure fails, in physical terms, in mutants with neural tube defects;
3. Determining the role of planar cell polarity (PCP) signalling, and downstream cytoskeletal events, in various aspects of body axis development, using several PCP mutants available in the lab;
4. Understanding the process of neural fold fusion, which is mediated by cellular protrusions from the neural fold tips, and the subsequent tissue remodelling which involves localised apoptosis;
5. Cell lineage tracing using DiI labelling and Cre-loxP-YFP transgenics to determine the origin of the neural plate from the multipotential tail bud cell population;
6. Determining the cellular role of folic acid, and related molecules, in promoting neural tube closure in mouse strains where defects are preventable by folates, as in some human cases.
Dr Nicolas Daudet
The sensory epithelia of the inner ear contain specialised ‘hair’ cells that are essential for hearing and our sense of balance. The disappearance of hair cells following acoustic trauma and during ageing is a very common cause of hearing loss because in mammals, lost hair cells are not replaced. By contrast, hair cells spontaneously regenerate throughout life in the inner ear of fish and birds. We are trying to understand the reasons for these differences by studying the cellular and molecular mechanisms controlling inner ear development and hair cell formation, using functional studies in chicken and mouse animal models.
Dr Patrizia Ferretti
The issue of neural injury in humans is of
key importance given the incapacitating effects of spinal cord or brain injury
and disease and their serious implications for both life quality in affected
individuals and long term care requirements. We are interested in gaining
further understanding of the mechanisms underlying the loss of regenerative
capability that occurs during development with a focus on events triggered
early after injury and the role of neural stem cells in the repair process. A
better understanding of these processes may help to devise strategies for decreasing
neural tissue damage by protecting neurones and glia from pro-apoptotic agents,
and aid neural repair by stimulating a more effective endogenous stem cell
response to injury. In recent proteomics and genomics studies comparing
regenerating and non-regenerating chick spinal cords, we have identified a
number of molecules/pathways which appear to be associated with changes in
regenerative capability. We have evidence that some of these molecules (e.g.
peptidylarginine deiminases) are important also in regulating death/survival of
human neural stem cells in response to injury in vitro. Projects will be
available to further elucidate the role of some of these pathways in normal
development and in response to an insult using chick injury models (e.g. spinal
cord injury, hypoxia) as well as human in vitro models mimicking the neural
stem cell niche, and to assess the neuroprotective potential of novel inhibitors
of peptidylarginine deiminases and of grafted somatic stem cells from different
sources. Students will gain expertise in a broad range of cellular and
Dr Alex Gould
It is well established that neural stem cells are influenced by local signals from niches, consisting of neighbouring glia, neurons and endothelial cells. However, it is not yet clear how they are regulated by dietary nutrients. It is not even known whether neural stem cells in vivo sense nutrient levels directly, via the niche or via intermediate systemic signals. This project will harness the advanced tissue-specific genetics possible in Drosophila. The aim is to find out how nutrients regulate the behaviour of neural stem cells (neuroblasts) in the physiological context of an intact animal. The starting point for the project are two recent studies (1,2) showing that, as neural stem cells age during development (3), they change from nutrient sensitive to nutrient-blind modes of growth. Underlying this transition is a corresponding switch in the type of signalling pathway that regulates growth - from one depending upon the Insulin-like receptor (InR) to another involving Anaplastic lymphoma kinase (Alk). The aim of this project is to identify the molecular pathways underlying the temporal switch in the nutrient sensing requirements of neural stem cells. Emphasis will be placed on determining the contributions from changes in the stem cell niche versus transitions within the neural stem cells themselves. The project will provide training in a wide range of techniques such as genetics, embryology, transgenesis, molecular biology, biochemistry, cell biology, confocal microscopy and bioinformatics.
1. Cheng, LY; Bailey, AP; Leevers, SJ; Ragan, TJ; Driscoll, PC and Gould, AP (2011). Anaplastic Lymphoma Kinase Spares Organ Growth during Nutrient Restriction in Drosophila. Cell 146, 435-47.
2. Sousa-Nunes, R; Yee, LL and Gould, AP (2011). Fat cells reactivate quiescent neuroblasts via TOR and glial insulin relays in Drosophila. Nature 471, 508-512.
3. Maurange, C; Cheng, L and Gould, AP (2008). Temporal transcription factors and their targets schedule the end of neural proliferation in Drosophila. Cell 133, 891-902
Prof Linda Greensmith
Heat shock proteins (Hsps) are a highly
ubiquitiously expressed family of stress response proteins
expression is increased in response to cellular stress.
heat-shock proteins (sHSP) family, which includes the 27
heat shock protein B1 (HSPB1), are defined by a low
and the presence of an 80–100 amino acid region known as
a-crystallin domain, which is thought to play a crucial
sHsp function. Several lines of evidence now indicate that
play an important role in neuronal function and survival
et al., 2002). Mutations in the Hsp27 gene lead to
in neurons with long axons, and in motoneurons in humans,
disruptions manifest as a group of disorders called distal
motor neuropathies (dHMN; Evgrafov et al., 2004). Hsp27 is
a potent promoter of axon regeneration in sensory neurons
the ability to support actin reorganization and therefore
growth (Hirata et al., 2003; Williams et al., 2006; Dodge
2006). However, our understanding of the molecular
underlie the role of Hsp27 in regenerating axons and how
in Hsp27 disrupt normal axonal function is very limited.
of this project is to characterize the role of Hsp27 on
using plasmid constructs expressing normal, wild type (WT)
Hsp27. Following transfection of neuronal cells with WT
Hsp27, we will examine the effect of various markers of
growth, maturation and survival. By assessing the effects
Hsp27 dysfunction in neurons transfected with mutant
Hsp27, we hope
to identify some of the key neuronal functions that are
on normal Hsp27.
Ackerley S et al., Hum Mol Genet 2006; (15): 347-354.
Dodge M E, et al., Res 2006; (1068): 34-48.
Evgrafov O V et al., Nat Genet 2004; (36): 602-606.
Hirata K et al., Glia 2003; (42): 1-11.
Kalmar B et al., Exp Neurol 2002; (176): 87-97.
Williams K L et al., J Neurosci Res 2006; (84): 716-723.
Dr François Guillemot
Most neurons of the brain are generated during
embryonic life but new neurons are added during adult life in the hippocampus, where they have an
important role in the acquisition of new memories. Hippocampal neurogenesis is
stimulated by physical activity and it declines with age, which has been linked
to the reduced cognitive performance associated with ageing in humans and mice.
The neural stem cells that generate new neurons in the hippocampus divide more
frequently in response to physical exercise while they become more quiescent as
animals grow older. We have recently discovered that the proneural transcription
factor Ascl1/Mash1 is essential for the division of neural stem cells in the
hippocampus (unpublished data), and we have identified the target genes that
Ascl1/Mash1 regulates in neural stem cells to promote divisions (Castro et al.,
2011). Which signalling pathways induce the expression of Ascl1/Mash1 in
hippocampal neural stem cells to promote neurogenesis is not known, although
there are some candidates, including the Igf (insulin-like growth factor) and
Shh (sonic hedgehog) pathways. The aim of this project is to identify the
signalling mechanisms that control the division of adult neural stem cells
through regulation of Ascl1/Mash1 expression, and to determine whether the
stimulation of neurogenesis by physical activity and its decline in old animals
are mediated by changes in Ascl1/Mash1 expression. Experiments will be
conducted in whole animals as well as in neural stem cell cultures and will
employ a broad range of molecular and genomic techniques.
Castro, D.S., Martynoga, B., Parras, C., Ramesh, V., Pacary, E., Johnston, C., Drechsel, D., Lebel-Potter, M., Galinanes-Garcia, L., Hunt, C., Dolle, D., Bithell, A., Ettwiller, L., Buckley, N., Guillemot, F. (2011). A novel function of the proneural factor Ascl1 in progenitor proliferation identified by genome-wide characterization of its targets. Genes Dev. 25, 930-945.
Prof Glen Jeffery
Our lab works on development and repair of
and visual pathways. Our aim is to understand basic
development and also to reveal through this the causes of
abnormalities. This involves embryological work on the
eye and brain in animal models and also when relevant,
this to clinical conditions.
We have a strong background in the tissue interactions in retinal development that regulate cell cycle, cell cycle exit and cell fate determination. Currently we are working on interactions between the neural retina and the retinal pigment epithelium (RPE). The latter contains a population of stem cells that are retained into maturity but locked in place by the neural retina. Unlocking these could mean that you activate your own stem cell population in response to ageing or damage. However, this can not be achieved unless we have a deeper understanding of the development of this region.
The lab is in a new building and highly productive. It consists of 6 postdocs and graduate students based in a very well resourced pure research environment. We are funded by the BBSRC and the Wellcome Trust. Please feel free to contact us if you would like to lean more about what we do.
Profs Kristjan R Jessen and Rhona Mirsky
To learn about the developmental and
events that allow myelinating Schwann cells of the
system to be generated from neural crest cells, we study
signalling in neural crest cells and between neurones and
examine how transcription factors control differentiation
and analyse intracellular signalling cascades that
proliferation, myelination and regeneration.
Previously, we identified the Schwann cell precursor, an intermediate in the Schwann cell lineage. This cell is multipotent, and can generate several different cell types. Its ability to survive and generate Schwann cells depends on the neuronal signal neuregulin, and the rate at which immature Schwann cells are generated from it is controlled by the Notch signalling pathway.
We are currently interested in understanding whether Numb, an antagonistic molecule associated with the Notch signalling pathway, has a role in maintaining the distinctive multipotent molecular and morphological phenotype of the Schwann cell precursor. Experiments to test this proposition would involve cell culture both in the presence and absence of DRG neurons and use of dominant-negative or ShRNA constructs to knock down Numb levels. Conditional mouse models in which Numb is selectively deleted in Schwann cell precursors would also be used. Morphological and molecular analysis of the resultant phenotypes would be carried out.
Woodhoo A, Sahni V, Gilson J, Setzu A, Franklin RJM, Blakemore WF, Mirsky R and Jessen KR (2007) Schwann cell precursors: a favourable cell for myelin repair in the Central Nervous System. Brain 130:2175-2185.
Wanner IB, Guerra NK, Mahoney J, Kumar A, Wood PM, Mirsky R and Jessen KR (2006) Role of N-cadherin in Schwann cell precursors of growing nerves. Glia 54:439-459.
Parkinson DB, Bhaskaran A, Droggiti A, Dickinson S, D'Antonio M, Mirsky R and Jessen KR (2004) Krox-20 inhibits Jun-NH2-terminal kinase/c-Jun to control Schwann cell proliferation and death. J Cell Biol 164:385-394.
Dong Z, Brennan A, Liu N, Yarden Y, Lefkowitz G, Mirsky R and Jessen KR (1995) NDF is a neuron-glia signal and regulates survival, proliferation, and maturation of rat Schwann cell precursors. Neuron 15:585-596.
Jessen KR, Brennan A, Morgan L, Mirsky R, Kent A, Hashimoto Y and Gavrilovic J (1994) The Schwann cell precursor and its fate: A study of cell death and differentiation during gliogenesis in rat embryonic nerves. Neuron 12:509-527.
Dr Nicoletta Kessaris
Interneurons in the adult cortex function as regulators of cortical
activity. They represent a heterogeneous population of cells in terms of
morphology, neurochemical and physiological properties. Our work aims to
understand how this diversity arises from neuroepithelial stem cells during
embryonic development. We recently used genetic manipulations in model
organisms to tag specific neuroepithelial populations with fluorescent proteins
and examine their cortical interneuron progeny during development and in the
adult forebrain. Using microarray analysis of purified immature interneuron
populations we identified a number of genes that may be involved in the
development and maturation of these cells. The involvement of cortical
interneurons in human diseases such as autism, schizophrenia and epilepsy, all
of which are considered neurodevelopmental disorders, opens up the possibility
of a role for these candidate genes in these disorders. The project will
involve gene expression analysis followed by functional studies
in mice using gain- and loss-of-function approaches.
Rubin AN, Alfonsi F, Humphreys MP, Choi CK, Rocha SF, Kessaris N. (2010) The germinal zones of the basal ganglia but not the septum generate GABAergic interneurons for the cortex. J Neurosci. 30(36):12050-62.
Nóbrega-Pereira S, Kessaris N, Du T, Kimura S, Anderson SA, Marín O. (2008) Postmitotic Nkx2-1 controls the migration of telencephalic interneurons by direct repression of guidance receptors. Neuron 59(5):733-45.
Fogarty M, Grist M, Gelman D, Marín O, Pachnis V, Kessaris N. (2007) Spatial genetic patterning of the embryonic neuroepithelium generates GABAergic interneuron diversity in the adult cortex. J Neurosci. 27(40):10935-46.
Keywords: CNS development, Cre-lox technology, interneurons
Prof Martin Koltzenburg
Chronic pain which is often
resistant to current treatments affects approximately 15% of the general
population including children. Pain is also an important neurobiological model
system and it is therefore of considerable interest to study the mechanisms that
determine the developmental emergence of nociceptors. These sensory neurons of
the peripheral pain pathway express unique sets of ion channels that endow them
with their remarkable ability to detect tissue damaging stimuli. Recent
research has shown that lack of function mutations of sodium channels or of
growth factor receptors such as the NGF receptor trkA leads to congenital
insensitivity to pain. Knowledge about these processes is crucial for the
discovery of novel medicines that combat pain. We investigate the functional
development of ion channels in sensory neurons with ratiometric calcium imaging
in novel compartmentalised cultures. We have shown that different nociceptor
subtypes develop in distinct waves starting in the mouse as early as E11.5
(corresponding to 6 weeks of human gestation) and extending well into the
postnatal period. We are currently investigating the role of neurotrophic
factors and pivotal transcription factors such as Runx1 for the developmental
emergence of transient receptor (TRP) ion channels such as the capsaicin
receptor TRPV1 that transduce painful stimuli and the emergence of different
types of sodium channels that are crucial for action potential propagation in
nociceptors rather than non-nociceptive neurons. Interestingly, while NGF is a
prototypical survival factor it is not capable to induce the expression of
TRPV1 channels. Knowledge from these studies will provide a better
understanding of hereditary neuropathies and chronic pain, areas of large unmet
medical need for novel therapeutics.
Hjerling-Leffler J, AlQatari M, Ernfors P, Koltzenburg M. Emergence of functional sensory subtypes as defined by transient receptor potential channel expression. J Neurosci 2007:2435-43.
Mantyh PW, Koltzenburg M, Mendell LM, Tive L, Shelton DL (2011) Antagonism of nerve growth factor-TrkA signaling and the relief of pain. Anesthesiology 115:189-204.
Park U, Vastani N, Guan Y, Raja SN, Koltzenburg M, Caterina MJ (2011) TRP vanilloid 2 knock-out mice are susceptible to perinatal lethality but display normal thermal and mechanical nociception. J Neurosci 31:11425-11436.
Schmalhofer WA, Calhoun J, Burrows R, Bailey T, Kohler MG, Weinglass AB, Kaczorowski GJ, Garcia ML, Koltzenburg M, Priest BT (2008) ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors. Mol Pharmacol 74:1476-1484.
Prof Alison Lloyd
The peripheral nervous system is one of the few tissues in the mammalian adult, which is capable of extensive regeneration. This process is all the more remarkable, in that repair can reconnect and re-establish fully transected nerves – requiring both the production of new tissue to bridge the gap between the nerve stumps and the accurate direction of regrowing axons back to their targets. Schwann cells are known to play a pivotal role in this process. In the adult, these highly specialised cells are normally in a quiescent state, myelinating larger axons or bundling together groups of smaller axons. Upon injury however, they dedifferentiate en masse to a progenitor/stem-like state and the proliferation and organisation of these cells is known to be critical for the repair process - for example by stimulating axonal growth. Schwann cell number and state is strictly controlled by the axon both during development and following repair. Imbalances in this tightly regulated system would be predicted to result in either degenerative disorders or hyperproliferative disorders such as cancer. Consistent with this view, Schwann cell tumours, especially neurofibromas, resemble an unrepaired wounded nerve, in that Schwann cells within the tumours are dedifferentiated and proliferate in the absence of axonal contact in a mixture of fibroblasts and inflammatory cells. How and why these differentiated cells retain this plasticity is unknown but a question of fundamental importance for regenerative medicine and for our understanding of Schwann cell tumourigenesis. In recent work, using a combination of powerful in vitro and in vivo model systems, we have explored the signalling pathways responsible for Schwann cell plasticity and how these are deregulated in cancer.
in the lab include the following
- Understanding the plasticity of the Schwann cell differentiation state
- Schwann cell/axonal interactions during repair and cancer
- Novel mouse models for studying tumour development in NF1
- Role of the microenvironment in the repair process and cancer
Simona Parrinello, Ilaria Napoli, Sara Ribeiro, Patrick Wingfield Digby, Marina Fedorova, David B. Parkinson, Robin D. S. Doddrell, Masanori Nakayama, Ralf H. Adams and Alison C. Lloyd. EphB signalling directs peripheral nerve regeneration through Sox2-dependent Schwann cell sorting. Cell 2010 143 145-155.
Simona Parrinello and Alison C Lloyd. Neurofibroma development in NF1 – insights into tumour initiation. TRENDS in Cell Biology 2009 19 395-403.
Simona Parrinello, Luke A Noon, Marie C Harrisingh, Patrick Wingfield Digby, Pedro Echave, Catherine A Cremona, Laura Rosenberg, Adrienne M Flanagan, Luis Parada and Alison C Lloyd. NF1 loss impairs Schwann cell-axonal interactions: a novel role for semaphorin 4F. Genes and Development (2008) 22, 3335-3348.
Harrisingh MC, Perez-Nadales E, Parkinson DB, Malcolm DS, Mudge AW and Lloyd AC. The Ras/Raf/ERK signalling pathway drives Schwann cell dedifferentiation. EMBO J (2004) 23, 3061-3071.
Mathon NF, Malcolm DS, Harrisingh MC, Cheng L, Lloyd AC. Lack of replicative senescence in normal rodent glia. Science (2001) 291, 872-875.
Dr Malcolm Logan
The limb is a model to study the
that regulate embryonic development, tissue/organ
has clinical relevance. Limb abnormalities are the second
congenital abnormality found in human live births.
as life expectancy increases the percentage of the
from age-related diseases of the musculoskeletal system is
The limb is a 3-dimensional structure comprised of multiple tissues (including bone, muscle, tendon) that are coordinated in an inter-connected network. The failure of any individual element to form normally during development or the deterioration of structures through ‘wear-and-tear’ has a debilitating effect on overall function of the entire limb.
The candidate will have the opportunity to use a range of experimental model systems, particularly the mouse, and novel mouse limb cell lines to investigate the factors regulating limb development and potentially important for regenerative medicine strategies. To generate limb progenitor cell lines, we have used embryos from transgenic reporter strains in which cells of the developing limb bud express fluorescent proteins or other markers. These reporters provide an easy to score and FACS sortable read-out of the cells identity. The cell lines will be used as source material for DNA microarray and RNAi screens.
Dr Robin Lovell-Badge
Tissue-specific progenitors play essential
for organ development and homeostasis but they are not
all tissues. Throughout life, the pituitary gland adapts
of its endocrine cell types to meet hormonal demands. This
may rely on adult progenitor cells and we have recently
such a population. These cells express SOX2, an HMG box
marker of several embryonic progenitors and stem cells,
‘pituispheres’ in culture, which can grow, self renew,
and differentiate to pituitary endocrine cells.
is associated with expression of SOX9, a related HMG box
SOX2+ve cells are found throughout Rathke’s pouch in
and persist in the adult gland. However most of these
cells also express SOX9.
This SOX2+ve/SOX9+ve population may represent transit amplifying cells, whereas the SOX2+ve/SOX9-ve cells could be progenitor/stem cells. To prove this hypothesis, we will better characterize the pituispheres, in particular by studying the role of SOX2 and SOX9 in vivo and in vitro. Conditional deletion alleles are available for both genes and we are developing genetic tools to specifically delete them in the Rathke pouch/pituitary; transient Cre expression in spheres will provide information in vitro. Characterization of such progenitor/stem cells will be of interest for stem cell based therapy in pituitary endocrine deficiencies.
Dr Juan Pedro Martinez-Barbera
My laboratory is focused on investigating
of Hesx1 in forebrain and pituitary development.
is important because mutations in Hesx1 are
with pituitary, eye and forebrain defects in mice and
research program aims to dissect the molecular pathways
controlled by Hesx1 during normal development.
lead to a better understanding of the pathogenesis of
where Hesx1 is mutated. Besides, it is a logical
to identify novel candidate genes, which might be mutated
suffering from pituitary, eye and forebrain defects.
Currently, there are two main lines of research: (i) The role of Wnt/beta-catenin signaling in anterior forebrain and pituitary development. We are exploring the relationship between this important signaling pathway and Hesx1. This study involves the use of conditional mouse models for components of this pathway, compound mutants, zebrafish experiments, microarray studies, in vitro assays, etc. Interestingly, this research has led us to study a particular type of cancer affecting the pituitary gland. (ii) The role of DNA methylation in mediating the HESX1-repressor activity. It seems likely that HESX1 mediates its molecular function by CpG methylation of target genes. This research aims to the identification of HESX1 targets and the study of CpG methylaton patterns in Hesx1+/+ and Hesx1-/- cells and embryos.
Experimentally, we combine mouse genetics (ES cell targeting, knock-in and knock-out mice), molecular biology and developmental biology techniques.
I will be very happy to accommodate one student in one of these ongoing projects.
1. Gaston-Massuet, C., Andoniadou, C.L., Signore, M., Sajedi, E., Bird, S., Turner, J.M.A. and Martinez-Barbera, J.P. (2008). Genetic interaction between the homeobox transcription factors HESX1 and SIX3 is required for normal pituitary development. Dev. Biol. DOI:10.1016/j.ydbio.2008.08.008.
2. Sajedi, E., Gaston-Massuet, C., Signore, M., Andoniadou, C.L., Kelberman, D., Castro, S., Etchevers, H.C., Gerelli, D., Dattani, M.T. and Martinez-Barbera, J.P. (2008). Accepted in Disease Models and Mechanisms.
3. Sajedi, E., Gaston-Massuet, C., Andoniadou, C.L., Signore, M., Hurd, P., Dattani, M. and Martinez-Barbera, J.P. (2008). DNMT1 interacts with the developmental transcriptional repressor Hesx1. Biochemica et Biophysica Acta (Molecular Cell Research) 1783, 131-143.
4. Andoniadou, C.L., Signore, M., Sajedi, E., Gaston-Massuet, C., Kelberman, K., Burns, A.J., Itasaki, N., Dattani, M. and Martinez-Barbera, J.P. (2007). Lack of the murine homeobox gene Hesx1 leads to a posterior transformation of the anterior forebrain. Development 134, 1499-1508.
5. Ivanova, A., Signore, M., Caro, N., Greene, N.D., Copp, A.J., Martinez-Barbera, J.P. (2005). In vivo genetic ablation by Cre-mediated expression of diphtheria toxin fragment A. Genesis 43, 129-135.
6. Dasen, J.S., Martinez-Barbera, J.P., Hernan, T.S., O’Connel, S., Olson, L., Ju, B., Tollkuhn, J., Buek, S.H., Rose, D.W. and Rosenfeld, M.G. (2001). Temporal switching of a paired-like homeodomain repressor/TLE corepressor complex for a related activator mediates pituitary organogenesis. Genes and Development 15, 3193-3207. Impact factor: 15.050.
7. Martinez-Barbera, J.P., Clements, M., Thomas, P., Rodriguez, T., Meloy, D., Kioussis, D., Beddington, R.S. (2000). The homeobox gene Hex is required in definitive endodermal tissues for normal forebrain, liver and thyroid formation. Development 127, 2433-2445.
8. Martinez-Barbera, J.P., Rodriguez, T.A., Beddington, R.S. (2000). The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation. Dev. Biol. 223, 422-430.
9. Dattani, M.H., Martinez-Barbera, J.P., Thomas, P.Q., Brickman, J.M., Gupta, R., Martensson, I.-L., Toresson, H., Fox, M., Wales, J.K.H., Hindmarsh, P.C., Krauss, S., Beddington, R.S.P., Robinson, I.C.A.F. (1998). Mutations in the homeobox gene Hesx1/HESX1 associated with septo-optic dysplasia in human and mouse. Nature Genetics 19, 125-133.
Prof Roberto Mayor
The Neural Crest (NC) gives rise to the
Nervous System, cartilage, bone and muscle in the face and
pigmented cells in the skin, several endocrine glands and
the heart. Two are the most astonishing characteristic of
its ability to migrate very long distances in the embryo
extraordinary ability to become many different types of
1. Migration of the NC Cells: Our aim is to identify the signals that control the initial delamination of the NC from the ectoderm, how the direction of migration is controlled and what stops NC migration once they reach its final target.
2. Differentiation of the NC Stem Cells. As the NC cells are able to originate a huge variety of different cell types it has been proposed that they have Stem Cell properties; however the molecular bases for these properties are unknown. Our aim is to identify the genetic cascade that controls the stem cell properties of the NC. Several screenings to identify new genes and candidate genes will be tested.
Both Projects will use Xenopus and zebrafish embryos and molecular and cell biology techniques (e.g. cloning, in situ hybridization, time lapse confocal video microscopy).
Dr Paola Oliveri
A fundamental question is to understand
program for the development of an organism is encoded in
DNA. During embryo development cells progressively
fate and get specified to become one or more cell types.
genes (transcription factors and signal transduction
are responsible for cell fate decision and are
in large networks, which execute the developmental program. Our goal is to study the gene regulatory network (GRN) underlying neuroectoderm specification in the sea urchin embryo to bridge genomic information and developmental events. Sea urchin has been proven to be an excellent experimental system for regulatory network studies. So far, the most comprehensive models for early
embryo development is the GRN for sea urchin endomesoderm. The GRN model will emerge from a system-level approach in which the regulatory genes involved during neuroectoderm development will be linked by cause-effect relationships. To this purpose the most advanced molecular biology, quantitative analysis and
classical embryology methodologies are used. A comparative analysis of sea urchin and vertebrate networks for neuroectoderm specification will identify commonalities that are essential for this cell type and principle of GRN modification.
Prof John Parnavelas
The ganglionic eminences of the mammalian
give rise to neurons destined for the cerebral cortex, basal
and olfactory bulb. The project will focus on the cell and
mechanisms that are involved in the sorting and migration of
into these three distinct brain areas.
Dr Franck Pichaud
During development, epithelial cells must evolve an apico-basal axis of polarity as well as discrete cell-cell contacts to enable organogenesis. Similarly, neurons are also highly polarized cells that differentiate their dendrites from the axon in order to enable neural circuit formation. Defective epithelial polarity is a hallmark of cancer and is thought to be a precursor of cell metastasis. Polarity defects during neuron migration and differentiation are thought to be contributing factors toward a number of neurodevelopmental conditions. There is therefore a strong impetus to elucidate the cellular and molecular basis for epithelial and neuronal differentiation, polarity and morphogenesis during development, as well as how these cells are maintained through adulthood.
1) Apico-basal polarity remodeling during development
A significant part of my group uses the developing pupal photoreceptor (PR) to elucidate the cellular and molecular basis for epithelial cell apical membrane differentiation, maturation and maintenance. This includes the elaboration of the apical most microvilli and sub-apical domain and the formation of the main apical cell-cell junction called the zonulaadherens (za). This part of our work is also designed to probe the interface between polarity proteins and global cell signaling (Pinal et al., Curr Biol., 2006; Richardson, Dev., 2010; Walther & Pichaud, Curr Biol., 2010; Pinal et al., JCS, 2011; Fichelson et al., PNAS, 2012).
2) Adherens Junction remodeling during organogenesis
A small team in my group uses the developing eye imaginal disc to elucidate the cellular and molecular basis for Adherens Junction (AJ) remodeling during organogenesis. Here we aim to integrate apical junction remodeling and associated cell shape changes together with cell division, apoptosis and differentiation. The wealth of prior knowledge that exists in the case of early compound eye morphogenesis makes this developmental context ideal for such an integrative study. More specifically, we would like to understand how apical cell constriction and regulated epithelial cell intercalation are orchestrated during retinal development to produce the crystal-like array of ommatidia that characterizes the compound eye. We have previously shown that in the developing retina, apical cell constriction is regulated by the Hedgehog (Hh) pathway (Corrigall et al., Dev Cell, 2007). In addition, we have recently established that the EGFR-signaling pathway governs AJ remodeling and associated cell intercalation during ommatidial patterning (Robertson et al., Dev., in press). We have shown that both of these instances of controlled apical junction remodeling are transcriptionally regulated downstream of Cubitusinteruptus for cell constriction and pointed for intercalatory behaviour respectively.
Neuronal differentiation and morphogenesis
An increasingly large part of my group is working on the problem of neuronal morphogenesis and polarity. Our approach is two fold: on the one hand, we have started to study the poorly understood role of transcriptional regulation during neuronal maturation and morphogenesis. On the other hand, we have begun to set up new approaches to uncover novel cellular and molecular mechanisms governing polarized axonal growth in vivo.
Dr Stephen Price
We are a group of Developmental
interested in how specificity is imparted during
the formation of functionally related neurons into
Since joining UCL at the end of 2003, we have focussed our
on a role for the cadherin family of cell adhesion
neuronal nucleus formation. Currently, we are studying
formation in the spinal cord and hindbrain, formation of
hindbrain nuclei and the formation of basal ganglia
We approach these problems from the hydrogen bond level
to the whole embryo. This broad approach is achieved in
our extremely productive collaborations with a group of
biologists at Columbia University in New York and with a
physicists in the Centre for Nanotechnology at UCL.
be interested in the references below and should contact
by emailing firstname.lastname@example.org
Patel, S. D., Ciatto, C., Chen, C. P., Bahna, F., Rajebhosale, M., Arkus, N., Schieren, I., Jessell, T. M. Honig, B., Price, S. R., and Shapiro, L. (2006) Crystal structures of type II cadherin ectodomains: Implications for the functional specificity of classical cadherins. Cell, 124, 1255-1268.
Price, S. R., DeMarco-Garcia N. V., Ranscht, B. and Jessell, T. M. (2002) Regulation of Motor Neuron Pool Sorting By Differential Expression of Type II Cadherins. Cell, 109, 205-216.
Prof Gennadij Raivich
Developmental injury to cerebral white matter and periventricular leukomalacia with white matter tissue necrosis and widening of cerebral ventricles are common causes of cerebral palsy and other neurological disabilities that affect 1-2/1000 babies. Although oxygen deprivation and infection around the time of birth are strongly associated with perinatal brain injury, this risk is particularly high in very preterm babies (<28 weeks of gestation), where a quarter or more of survivors will develop spastic motor deficits and severe cognitive and behavioural abnormalities. Recent studies in our laboratory point to strong involvement of activated phagocytic macrophages in the periventricular fountains of microglia – (a) fetal and neonatal white matter is particularly sensitive to inflammation-induced as well as hypoxic-ischemic brain damage, (b) the endogenous period of endogenous phagocytic macrophage activation coincides with the period of white matter sensitivity, and (c) periventricular macrophages are first to be activated even after very mild hypoxic insult. The proposed project will use transgenic mice targeting microglial signalling pathways (ERK, JNK, MyD88, TREM, src/syk) and pharmacological agents to determine molecules involved in macrophage deactivation and response to injury, and their effects on preventing subcortical white matter damage in the fetus and neonate.
Dr Antonella Riccio
Within the nervous system, neurotrophic factors and activity regulate a wide range of processes including the proliferation of neuronal precursors, and the growth, survival, and synaptic connectivity of developing neurons. Many, if not all of the stimuli that contribute to such processes have the capacity to signal to the nucleus and influence gene expression. Our laboratory is interested in understanding the transcriptional and epigenetic mechanisms that regulate gene expression in neurons. We will use in vivo and in vitro models to address 1) the role of the transcription factor CREB in the adult and developing nervous system 2) characterize a novel signalling pathway that controls neuronal gene expression by inducing epigenetic changes 3) identify RNA transcripts locally translated in axons.
Prof Bill Richardson
It used to be thought that, once the brain was fully developed, no further neurogenesis occurred during adult life. This is now known to be wrong; neural stem cells persist in the subventricular zones (SVZ) of the adult forebrain and the dentate gyrus of the hippocampal formation and these continuously generate new neurons that integrate into the olfactory bulb and hippocampus, respectively. It is not certain what the function of the new neurons is but they are believed to be required to lay down new olfactory and spatial memories. There is another population of cells with stem cell-like properties – so called “adult oligodendrocyte precursors (adult OLPs)”, which are distributed widely and uniformly through the brain and spinal cord. We have recently shown that these continuously generate new oligodendrocytes (the myelinating cells) and - more surprising - small numbers of pyramidal neurons in the adult cerebral cortex. We do not know where these neurons project to, or whether they become myelinated and participate in normal brain function. We also do not know whether neuron production is increased by environmental enhancement or exercise – both of which are known to stimulate production of new hippocampal neurons – or in response to neuronal loss caused by injury or disease. The student will investigate these questions using a range of approaches including mouse transgenesis, histology and behavioural tests.
Prof Christiana Ruhrberg
VEGF-A is secreted protein that controls blood vessel growth. We and others have shown that VEGF-A also has essential functions in neurons of the central nervous system (CNS). In addition, my laboratory discovered that VEGF-A contributes to the development of glial cells in the peripheral nervous system (PNS). This project will explore the role of VEGF-A in the growth and differentiation of a glial cell type termed the boundary cap cell (BCC). BCCs cluster at the PNS/CNS interface to help spinal sensory axons enter the CNS. BCCs do not persist into adulthood, which may contribute to the failure of sensory axons to regenerate into the spinal chord after injury. However, BCCs can be isolated from embryos and passaged indefinitely; moreover, they can be induced to differentiate into different types of PNS neurons. Thus, BCCs are embryonic stem cells with therapeutic potential in nervous system regeneration. Our pilot data show that VEGF-A signalling is essential for BCC development. Taken together with the observation that VEGF-A promotes neuronal and blood vessel growth, we believe that VEGF signalling may be exploited as a versatile molecular tool to repair damaged nervous tissue by simultaneously promoting the formation blood vessel, neurons and boundary caps.
Prof Patricia Salinas
The formation of neuronal circuits requires the proper assembly of functional synapses. After the peak of synaptogenesis, refinement of connections occurs where many synapses are eliminated through a process of dendritic and axonal pruning. This normal process of refinement requires the proper balance between formation and elimination of synapses, which is crucial for the structural and functional assembly of complex neuronal circuits. Our lab is elucidating the mechanisms that regulate the formation and maintenance of synapses in the adult mouse brain. In particular, we are studying the role of Wnt signalling molecules. We found that Wnts regulate axon terminal remodelling, a process that contributes to the conversion of growth cones into synaptic boutons. Wnts also stimulate dendritic arborization and synaptic assembly. More recently we found that Wnts also regulate the maintenance of synapses. Therefore, we are investigating how Wnts contribute to establish a balance between synapse formation and elimination. As Wnts stimulate the proliferation and survival of stem cells in the adult mouse hippocampus, we are also examining whether Wnts influence synaptic connectivity through stem cell proliferation and/or survival in the hippocampus. We use a combination of state-of-the-art 4D imaging techniques, transgenesis, electrophysiological recordings and behavioural tests.
Dr Jane Sowden
This project aims to promote stem cell cultures to differentiate to produce new photoreceptors for repair of the retina. Retinal diseases leading to the loss of rod and cone photoreceptor cells are major causes of irreversible blindness. As the retina is unable to regenerate itself, replacement of lost photoreceptors by transplanting new cells into the retina is one possible therapeutic approach. We recently discovered that immature cells taken from the peak stage of rod photoreceptor development, when the retina is forming, can be successfully transplanted and restore some vision in models of retinal disease (see Nature, 2006. 444: p. 203-7). Our experiments show that the mature retina, previously believed to have no capacity for repair, is in fact able to support the development of new rod photoreceptors. As many retinal diseases, including those causing childhood blindness, affect the cone-rich macular region of the retina that provides high visual acuity and colour vision, this project will investigate whether we can develop new cone photoreceptors from in vitro stem cell cultures for retinal repair. Fluorescent transgene reporters will be used to identify retinal progenitor cells, and based on knowledge of retinal development, the genes promoting photoreceptor differentiation will be induced by manipulation of signalling pathways. This exciting project will provide the successful candidate with a broad training and expertise in retinal development and experimental models of retinal disease, transgenesis, stem cell biology, molecular biology, cell culture and histology techniques.
Dr Philip Stanier
Orofacial defects, particularly clefts of
or palate are among the most common human birth defects
The molecular pathways that lead to these craniofacial
are largely unknown. Mutations in the gene encoding the
factor TBX22 on the X-chromosome were first identified in
and still represent one of very few known genetic causes
cleft palate. Cleft palate can arise as a consequence of
shelf outgrowth from the maxillary prominence, a failure
and correctly align above the tongue, failure during shelf
and/or epithelial seam degeneration or failure in
formation in the hard palate. It is rarely possible to
which of these is affected by the time the defect is
birth. We are therefore investigating the anatomical and
defect underlying X-linked cleft palate in a mouse model
deficient for Tbx22. In the majority of animals, the
appear to grow and fuse normally but lack appropriate
of the posterior bones of the hard palate, giving rise to a
cleft palate. This project aims to investigate the failed
mechanisms that are normally required for palatine bone
Braybrook et al. X-linked cleft palate and ankyloglossia (CPX) is caused by mutations in the T-box transcription factor gene TBX22. Nat Genet 2001 29: 179-183.
Stanier P and Moore GE. Genetic basis for cleft lip and palate: syndromic genes contribute to the incidence of nonsyndromic clefts. Hum Mol Genet 2004 13: R73-R81.
Andreou et al. TBX22 missense mutations found in patients with X-linked cleft palate affect DNA binding, sumoylation and transcriptional repression. Am J Hum Genet 2007 81: 700-712.
Prof Claudio Stern
The research in our laboratory focuses on the processes that establish cell diversity and pattern in the early embryo. We ask the questions: how do cells in the embryo know what fates to adopt, at the right positions and at the right time? What mechanisms ensure that the correct proportions of cells are allocated to different organs? Currently, the projects in the lab fall into four major headings: 1. How do higher vertebrate embryos establish their polarity, and what mechanisms coordinate cell movements with gene expression? 2. What mechanisms are responsible for inducing the early nervous system? 3. How is the early nervous system subdivided into forebrain, midbrain, hindbrain and spinal cord? 4. Embryonic stem cells - where are they in the embryo, and can we harness them to understand developmental pathways?
Dr Masa Tada
Several distinct cell movements shape the
body axis during vertebrate gastrulation. Presumptive
plate cells undergo directed anterior migration as a
of cells, whereas dorsal mesodermal cells undergo
extension, co-ordinated movement mediated by a large sheet
There is emerging evidence that a signalling pathway
the planar cell polarity (PCP) pathway of flies
contributes to the
co-ordination of cell behaviours in several events in
and this pathway is required for gastrulation
movements1-3. We use
the zebrafish as a model system to understand cellular and
mechanisms underlying the co-ordination and directionality
gastrulation movements. The objectives of this project
are: 1) How
do distinct cell populations mediate their directionality?
do PCP proteins correlate with the direction of cell
To address these questions, we will undertake a
to visualise cell behaviours and protein localisations in
embryo using Green/Red fluorescent protein-tagged proteins
on sophisticated transgenic and time-lapse confocal
1. Tada et al. (2002) Semin Cell Dev Biol 13, 251-60 (review).
2. Carreira-Barbosa et al. (2003) Development 130, 4037-46.
3. Witzel et al. (2006) J Cell Biol, 175, 791-802.
Dr Jean-Paul Vincent
Embryonic development is an amazingly reliable process. Most embryos
give rise to fully patterned organisms with great accuracy. One process that
contributes to such accuracy is the elimination of mis-specified or defective
cells during development. Such elimination is evident in patterning mutants,
where cell death is often observed. For example, as shown in the figure,
extensive apoptosis is seen in fushitarazu
(ftz) mutants of Drosophila. Importantly, ftz is not required for cell survival per se. Indeed, it can be
knocked down from cultured cells without deleterious effect. However it is
likely that the absence of Ftz during development will cause many cells to
express a non-sense combination of developmental regulators. We predict that
there is machinery that detects such non-sense and triggers apoptosis as a
result. We propose to take advantage of the power of Drosophila genetics to
identify components of this hypothetical machinery. We
already know that hid, a key
proapoptotic gene, is transcriptionaly upregulated in ftz (and other
developmental) mutants. Moreover, Hid is required for apoptosis to take place
in ftz mutants. Therefore, we can
reduce our aim to the identification of genes that are required for hid upregulation in developmental
mutants. To this end, we will first devise a reporter of hid transcription (using genomic engineering and/or BAC
recombineering). We will then use a deficiency collection (comprising about
1000 lines that collectively uncover about 90% of the genome) to screen for
genes that are required for upregulation of the hid reporter in ftz
mutants. Once such genes are identified, we will ask if they encode general
components of apoptosis or whether they are specifically required for the
elimination of mis-specified cells. We hope to decipher how the latter
contribute to the recognition of mis-specified cells and possibly uncover a
novel mechanism of quality control within tissues.
Prof David Whitmore
As part of our ongoing studies on the circadian clock in zebrafish, we are interested in exploring the role played by this cellular clock in the earliest stages of embryo development. We know that the clock starts to oscillate in these animals during the first day of development, and that cells in the embryo are able to detect light within hours of fertilization. What exactly light and the clock are directly regulating during development is not yet totally clear. However, we do know that one consequence of this innate rhythmicity is to regulate the timing of cell cycle events, such as DNA replication and mitosis, such that they occur primarily in the night. This contrasts to DNA repair events, which occur mainly during the day. These studies will involve the generation of transgenic animals containing luminescent reporter constructs so that we can image gene expression in the living embryo as it undergoes development. In addition, we will employ microarray analysis of early embryos in an attempt to determine the cellular processes directly influenced by light exposure.
Prof David Wilkinson
During early stages
of nervous system development in vertebrates, neural tissue is subdivided into
building blocks, each with a distinct regional identity. Within these
subdivisions, the proliferation and differentiation of progenitor cells is
regulated in time and space to form the correct number and organisation of
neuronal and glial cells. In order for these precise patterns to form and be
maintained, it is essential that cells do not migrate into inappropriate
locations. Disruption of the mechanisms that regulate cell proliferation,
differentiation or migration can lead to diseases such as cancer.
Our studies focus on the zebrafish hindbrain, which has a stereotyped segmented organisation of progenitors and neurons, to address two linked questions: how do sharp borders form and the interface of segments?; how is the differentiation of neural progenitors patterned within segments? These studies utilise the advantages of the zebrafish model for genetic manipulation and for imaging of cell behaviour. We are analysing how signaling through Eph receptors and ephrins inhibits intermingling and establishes sharp boundaries between distinct cell populations. In other studies, we have identified a pathway mediated by targeted protein degradation required for the onset of neuronal differentiation, and uncovered a novel mechanism underlying spatial patterning of neurogenesis involving FGF signaling from neurons.
Gonzalez-Quevedo R, Lee Y, Poss KD and Wilkinson DG (2010) Neuronal regulation of the spatial patterning of neurogenesis. Developmental Cell 18, 136-147
Sobieszczuk DF, Poliakov A, Xu Q and Wilkinson DG (2010) A feedback loop mediated by degradation of an inhibitor is required to initiate neuronal differentiation. Genes & Development 24, 206-218
Terriente J, Gerety SS, Watanabe-Asaka T, Gonzalez-Quevedo R and Wilkinson DG (2012) Signalling from hindbrain boundaries regulates neuronal clustering that patterns neurogenesis. Development 139, 2978-2987
Batlle E and Wilkinson DG (2012) Molecular mechanisms of cell segregation and boundary formation in development and tumorigenesis. Cold Spring Harbor Perspectives in Biology 4, a008227
Prof Stephen Wilson
Using the zebrafish as a model system, we are studying patterning, morphogenesis and differentiation in the forebrain. One focus is to examine the mechanisms by which stem cells and progenitors transition to differentiated neurons in the eye and in the epithalamic region of the dorsal forebrain. The epithalamus is highly asymmetric between left and right sides and we have made progress in defining the signalling pathways involved in the generation of asymmetry and how such asymmetry is manifest at the level of neuronal morphology and connectivity. We have found that Fgf and Wnt signals are important for elaboration of epithalamic asymmetries but it remains uncertain how and what these pathways are doing. One potential project will be to analyse how these signalling pathways influence the production of neurons with different character between left and right sides of the brain. We are also studying how stem cells are maintained at the margin of retina and another project could be to study the role of extracellular matrix and extrinsic signals in the regulation of proliferation and differentiation in the retinal stem cell niche. Both projects would involve a broad range of molecular genetic techniques coupled with high resolution imaging approaches (www.ucl.ac.uk/zebrafish-group/).
Dr Yoshiyuki Yamamoto
About 20 million children suffer from congenital and inherited eye malformations, with most defects occurring in the lens and its related parts of the anterior segment. The insertion of an intraocular lens (IOL) is a routine part of cataract surgery in adults, even in many developing countries. However, the IOLs often suffer with the development of secondary cataracts due to the proliferation of lens epithelial cells left in the lens capsule. Also, insertion of an IOL into a child can be a difficult procedure, and if there are serious complications, the vision may be permanently lost. Lens regeneration could be the ultimate therapy for cataracts. Rabbits and cats are able to regenerate their lenses upon removal, but only if the anterior and posterior capsular bags are left intact. The regenerates seem to be generated from growth of lens epithelial cells left in the capsular bags. In zebrafish and Mexican tetra Astyanax eyed surface fish, we found that lens epithelium cells can regenerate intact lens. However, the lens form Astyanax eyeless cavefish or from two lens mutants of zebrafish couldn’t regenerate. In this proposal we will use several different model organisms (cavefish, zebrafish, frog, chick and mouse) to find out the mechanisms of the lens regeneration In Vitro and Vivo. We have a tight collaboration with Professor Shin-ichi Ohnuma at Institute of Ophthalmology at UCL in this project.
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