Role of NeuroD family genes in the control of neocortical layering

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Correct assembly of neuronal circuits is vital for the function of the adult brain. Cerebral cortex is the crown of mammalian evolution and is probably one of the most complex organs. Neuronal bHLH transcription factors of the NeuroD family (Neurod1, Neurod2, and Neurod6) are expressed in young neurons of the dorsal telencephalon and have long been speculated to play an important role in neuronal determination and differentiation. However, their function in the development of the mammalian cerebral cortex has not been investigated so far. High sequence similarity in the bHLH domain and highly overlapping expression patterns in the developing neocortex suggested function redundancy. In order to overcome the latter, we generated compound mutant mice where all three genes were deleted.Our preliminary work has uncovered several interesting phenotypes in NeuroD triple mutants. Animals deficient for NeuroD1, Neurod2, and Neurod6 in the neocortex show strong deficits of neuronal differentiation and cerebral cortex cytoarchitechture.To understand these phenomena we propose a full spectrum characterization of Neurod1/2/6 triple mutants. This involves morphological characterization, neuronal migration analysis, investigation of cell fate determination as well as cell survival and neuronal progenitors proliferation. We also aim to identify molecular mechanisms downstream of Neurod genes that control these processes in the developing cerebral cortex. Our proposed study of NeuroD–deficient neurons in the cerebral cortex aims to provide valuable insights into the molecular basis of cerebral cortex development.