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4 YEAR PhD IN NEUROSCIENCE

Juan Pedro Martinez-Barbera

Early forebrain patterning in mammals

We are interested in the early stages of embryonic brain development. Soon after gastrulation the early neural plate is specified in distinct domains fated to give rise to the fore, mid and hindbrain in the adult. We are investigating the molecular mechanisms underlying forebrain specification with the main goal of better understanding the pathogenesis of human congenital conditions affecting this structure. Close collaborations with clinicians at Great Ormond Street Hospital for Children allow us to put our basic research in a clinical context.

Available rotation projects

1. We have demonstrated an essential role for the homeobox transcriptional repressor HESX1 in the specification of the anterior forebrain. Cells fated to populate the anterior forebrain (i.e. the cerebral hemispheres) change identity and colonise more posterior regions of the brain in Hesx1-deficient embryos. We have recently shown that this is done in conjunction with another repressor (TCF3), but the molecular mechanisms were not fully elucidated.

We are planning to generate molecular chimeric constructs expressing HESX1 fused to tag epitopes to facilitate the isolation of HESX1 targets and protein partners. The student will get involved in the generation of these chimeric constructs and the assessment of their biological activities in vitro. This will require PCR amplification, DNA cloning, cell transfection, protein extraction and western blotting, among other techniques.

2. Mutations in HESX1 underlie a human condition called Septo-Optic-Dysplasia (SOD), a syndrome characterised by defects in midline forebrain structures, optic nerve hypoplasia and hypopituitarism. So far, more than 16 different mutations have been identified in humans with this condition. The mechanisms underlying optic nerve hypoplasia are not understood.

We are interested in the role of HESX1 in optic nerve development. HESX1 is not expressed in the optic nerve but we have evidence showing that it is expressed in optic nerve precursors. The student will use genetic tools already available in the lab to explore this hypothesis. Technically, this project will involve histology, immunostaining and in situ hybridisation among other techniques.

Selected publications

Andoniadou, C.L., Signore, M., Young, R.M., Gaston-Massuet, C., Wilson, S.W., Fuchs, E. and Martinez-Barbera, J.P. (2011). HESX1 and TCF3 mediated repression of Wnt/beta-catenin targets is required for normal development of the anterior forebrain. Development 138, 4931-4942.

Gaston-Massuet, C., Andoniadou, C.L., Signore, M., Jayakody, S.A., Charolidi, N., Kyeyune, R., Vernay, B., Jacques, T.S., Taketo, M.M., Le Tissier, P., Dattani, M.T. and Martinez-Barbera, J.P. (2011). Increased Wingless (Wnt) signaling in pituitary progenitor/stem cells gives rise to pituitary tumors in mice and humans. Proc. Natl. Acad. Sci. USA 108, 11482-487.

McCabe, M.J., Gaston-Massuet, C., Tziafari, V., Gregory, L.C., Alatzoglou, K.S., Signore, M., Puelles, E., Gerrelli, D., Farooqi, I.S., Raza, J., Walker, J., Kavanaugh, S.I., Tsai, P.S., Pitteloud, N., Martinez-Barbera, J.P. and Dattani, M.T. (2011). Novel FGF8 mutations associated with recessive holoprosencephaly, craniofacial defects and hypothalamo-pituitary dysfunction. Journal of Clinical Endocrinology and Metabolism 96(10):E1709-18.

Longbottom, R.E., Fruttiger, M., Douglas, R.H., Martinez-Barbera, J.P., Greenwood, J. and Moss, S.E. (2009). Genetic ablation of retinal pigment epithelial cells reveals the adaptive response of the epithelium and impact on photoreceptors. Proc. Natl. Acad. Sci. USA.106, 18728- 85.

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). Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism. Disease Models and Mechanisms 1, 241-254.

Abrahamsen, B., Zhao, J., Asante, C.O., Cendan, C.M., Marsh, S., Martinez-Barbera, J.P., Nassar, M.A., Dickenson, A.H., Wood, J.N. (2008). The cell and molecular basis of mechanical, cold, and inflammatory pain.Science 321, 702-705.

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. 324,322-333.

Martinez-Barbera J.P., Rodriguez T.A. and Beddington R.S. (2000). The homeobox gene Hesx1 is required in the anterior neural ectoderm for normal forebrain formation. Dev. Biol. 223, 422-430.

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. and 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.

More information:

http://www.ucl.ac.uk/ich/research-ich/neural-development/research

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