The greatest differences between mammals are size. As well, the large evolutionary expansion of the cerebral cortex is a defining feature humans. Despite this, much remains to be learnt about the developmental and evolutionary factors controlling organ and organism size. This is in marked contrast to the exquisite detail in which developmental patterning has been defined in model organisms. The identification of genes for human disorders of extreme growth failure (microcephalic primordial dwarfism) provides a means to gain new insights into the regulation of human brain and body size. I have identified eight genes regulating cerebral cortex volume and organism size, all of which encode fundamental components of cell machinery regulating cell division. This proposal aims to ascertain the genes causing the other 85% of primordial dwarfism, and define their cellular and developmental functions. The central hypothesis for the proposed work is that such primordial dwarfism and microcephaly genes are components of common cellular pathway(s) relevant to organ and organism growth. I propose to pursue complementary approaches involving human disease gene identification, cell biology studies, and model organisms, to address this hypothesis and further define the pathogenesis of these conditions. These cross-disciplinary studies will contribute to our understanding of vertebrate growth regulation and help us understand how the human brain evolved. They may provide insights into neural stem cell division relevant to brain repair. Finally and not least, regulation of DNA replication, centrosome function and DNA damage response signalling are key cellular processes perturbed in many important human diseases, from developmental disorders to cancer.
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