Research
Research in this unit is concerned with the following areas of developmental biology:
- Development and regeneration of the nervous system
-
- Craniofacial development and repair
- Midline Defects (joint Neural Development Unit)
- Eye Diseases
- Orofacial development Group
Development and Regeneration Group
Group Leader: Dr. Patrizia Ferretti
One major research interest concerns the origin of neural progenitors and the environmental conditions in which regeneration of the nervous system can takes place (e.g. role of certain growth factors such as members of the FGF family). A thorough understanding of the mechanisms underlying tissue and organ regeneration in the different models we are currently using my help to devise strategies for restoring functionality in damaged or diseased human tissues either by stimulating endogenous neural stem cells or by cell grafting approaches.
Another major theme is the skeletogenic differentiation of the neural crest in relation to normal and abnormal skull morphogenesis with a particular focus on the role of the transcription factor twist and of fibroblast growth factor receptors. Recent interests include the possibility of using osteoprogenitors from patients with craniosynostosis (bone biopsies provided by clinical colleagues at GOS) seeded on bioabsorbable scaffolds.
Overall, both the work on neural regeneration and on normal and abnormal craniofacial development / regeneration going on in the laboratory focus on the issues of cell plasticity and differentiation potential, and the role of FGF signaling in these processes. A multidisciplinary approach and a broad range of cellular and molecular techniques are used to address these important issues.
Several
current laboratory-based projects (e.g. molecular mechanisms underlying
craniosynostosis and cranial bone repair) are closely integrated with
the clinical research interests of clinical and surgical colleagues at
Great Ormond Street Hospital.
Ongoing Projects
- Cellular and molecular basis underlying changes in regenerative capability in the developing spinal cord
- Role of peptidylarginine deiminases in neural progenitors in health and disease
- Establishment of 3D models for the study of human neural cells
- Adipose-tissue derived stem cells for craniofacial and neural repair
- Role of the choroid plexus in the developing brain
- Neural stem cell labelling and tracking with magnetic resonance imaging
Undifferentiated (left) and differentiating (right) human neurospheres
In vivo monitoring by MRI of NT2 neural stem cells labelled with
ultrasmall superparamagnetic iron oxide (USPIO) particles (Sinerem) 14
days following stroke and cell injection (collaborative work between P.
Ferretti and J. Sowden in the Developmental Biology Unit, M. Lythgoe and
D. Gadian in the
and J. Steinke at Imperial College,
London)
Neurofilament-positive axonal swellings (arrowhead) are abundant in E15
damaged chick spinal cord but not in E11 cords (not shown).
Motor neurons retrogradely labelled from muscle (red) migrate into
the regenerating spinal cord of tailed amphibians.
Expression of the transcri[ption factor Snail mRNA in fusing palatal
shelves after 48 hours (hrs) in culture (t, tooth bud,; N, nasal side;
O, oral side)
Eye Development and Repair Group
Group Leader: Dr Jane Sowden
Research
in the eye development and repair group aims to identify the genetic
pathways underlying normal eye development and to understand how
mutations in key genes cause eye malformation and disease. Our research
is focussed on understanding the developmental regulation of ocular stem
and progenitor cells that offer the potential for repair and
regeneration of diseased eye tissue.
In the UK, 1 in
every 1,000 children are visually impaired or blind. More than a quarter
of all cases are caused by congenital eye defects. These include the
condition microphthalmia, in which the embryonic eye fails to grow,
conditions involving malformations of the anterior segment of the eye
and glaucoma, and conditions involving abnormal development and
degeneration of photoreceptor cells. Congenital eye defects are often
found in association with other non ocular malformations and children
with these syndromes are frequently seen by clinical colleagues at Great
Ormond Street Hospital for Children NHS Trust.
Mutations in
genes encoding transcription factors are the most common known cause of
congenital eye defects. To improve understanding of the aetiology of
these conditions, a range of experimental approaches (molecular biology,
embryology, cell biology, genetics) are being used to explore the
function and interactions between key transcription factors during eye
development. The prevalence of different types of genetic change in
affected individuals is being analysed to improve diagnosis and identify
asssociated risk factors.
A central research theme is study
of the molecular mechanisms regulating proliferation of retinal
stem/progenitor cells and the generation of retinal neurons from these
progenitor cells.
Research includes investigation of
embryonic retinal progenitor cells and retinal stem/progenitor cells
derived from the adult eye. We have recently shown that transplanted
photoreceptor precursors can improve visual function in animal models of
retinal disease. We are pursuing development of retinal stem therapy
for the treatment of retinal disease in collaboration with Professor
Robin Ali at
Adult-derived
retinal stem cells are potentially useful as a source of new neurons
for treatment of retinal disease. Identification of genetic pathways
and environmental conditions that are sufficient to promote production
of new retinal neurons from retinal stem cells is an important current
goal.
Ongoing projects
- Retinal stem cells and their potential for treatment of retinal disease
- A study of microphthalmia and the role of the Chx10 gene in retinal progenitor cells
- Altered gene dosage as a mechanism for congenital eye defects and glaucoma
- Molecular genetic analysis of glaucoma and abnormal development of the anterior segment of the eye
- Analysis of the role of T-box genes in patterning and development of the retina and nervous system
Proliferation of retinal progenitor cells in the optic cup is reduced by
lack of the Chx10 transcription factor. Phosphohistone H3
immuno-labelling of mitotic retinal progenitor cells (green) at the
ventricular surface in the embryonic eye. +/+ is a normal eye and -/- is
a microphthalmic eye lacking Chx10.
Retinal stem cells isolated from the ciliary epithelium of the adult
ciliary body proliferate and form neurospheres in culture.
Immuno-labeled with the progenitor cell marker, nestin (green).
Molecular patterning across the dorso-ventral axis of the embryonic eye. Tbx5 gene expression (blue) is restricted to retinal progenitor cells in the dorsal peripheral region of the developing optic cup.
Transplanted photoreceptor precursor cells integrate and develop into mature photoreceptor cells (green) that form functional connections with the host retina (blue) and improve visual function [see MacLaren, Pearson et al Nature 2006; 44:203-7].
Transplanted cone photoreceptor (yellow) within the outer nuclear layer
(magenta) of a recipient retina [see Lakowski, Baron et al (2010) Hum. Mol.
Genet. doi:10.1093/hmg/ddq378.]
Orofacial development Group
Group Leader: Dr Agnès Bloch-Zupan
We are interested in the molecular mechanisms underlying normal mammalian craniofacial development (ie palate and tooth) and why and how some genetic and/or external factors, like retinoic acid, may modify the normal progression of developmental events leading to clinical defects like cleft palate or tooth abnormalities.
We are focusing on genes involved in human diseases whose clinical synopses result in these defects. In particular we are interested in the twist and OFD1 genes that when mutated cause Saethre Chotzen syndrome and oral-facial-digital syndrome type 1, respectively.
Ongoing projects
- Analysis of craniofacial anomalies from a clinical, genetic and developmental point of view.
- Role of retinoid signalling in mouse palatogenesis.
Midline Defects Group
Group Leader: Dr Philip Stanier
Interests
include study of the genetic pathways and underlying molecular events
that lead to common birth defects such as cleft palate, neural tube
defects and IUGR.
Page last modified on 20 mar 11 09:22
