The evolutionary expansion of the human neocortex required increased production of excitatory and inhibitory neurons. The balance between excitation and inhibition is critical for normal neurological function, and yet we know little about the human-specific genetic changes underlying increased neurogenesis. The recent availability of complete genome sequence from humans and a diverse range of mammals makes large scale sequence comparisons possible. Regulatory elements that are conserved in other mammals, but surprisingly missing in humans could contribute to human specific biology. Initial work on the project shows that humans have lost a forebrain specific regulatory element in zones of inhibitory interneuron production near the tumor suppressor gene GADD45g, which is specifically expressed in neural progenitors during development. GADD45g represses cell cycle in culture and GADD45g down-regulation is strongly associated with pituitary adenomas, yet the function of GADD45g in nervous system development has not yet been explored. This project will characterize in detail the neuronal lineages affected by the human specific genetic change using genetic labeling techniques in mouse stable lines expressing Cre-recombinase driven by the enhancer missing in humans. To put the mouse expression data in the context of changes in primate gene regulation, this project will also identify the upstream regulators of the DNA sequence that is missing in humans. Finally, this project will characterize how loss of the GADD45g gene affects brain development in mouse using an existing knockout line not previously analyzed for nervous system phenotypes. Collectively, these experiments will provide an in depth study of how a human- specific genetic change may contribute to specialized aspects of human brain development.
This research is relevant to public health because GADD45g mis-regulation is strongly associated with multiple cancers including pituitary adenomas, a major form of brain cancer. Additionally, the balance between neuronal excitation and inhibition is critical for normal neurological function and may be disrupted in disorders as diverse as epilepsy, Down's syndrome and autism. Identifying how human specific genetic changes regulating GADD45g expression affect the production of inhibitory interneurons may both aid in understanding the role of GADD45g in human brain tumors, and in understanding uniquely human aspects of inhibitory neuron production.
