| The highly specialized functions of the mammalian cerebral cortex rely on the temporally precise development and organization of diverse cell types by various cellular processes. However, a complete understanding of the molecular mechanisms that regulate these events is still lacking. Here, I implement Mus musculus as a model system for studying neocortical development, given that many processes and genes involved in brain development are conserved from mouse to human. In this thesis, I primarily present results from a detailed characterization of transcription factor, Nuclear Factor One B (NfiB ), during mouse neocortical development. Additionally I have included a short discussion regarding my contributions toward understanding how another transcription factor, Fezf2, functions as a key fate determinant of subcerebral neuron identity. NFIB is expressed in the cortical proliferative zone and in a subpopulation of cortical projection neurons. Given its expression pattern within the cerebral cortex and previously identified functions in CNS development, we hypothesized that NfiB was a key regulator of neocortical development. Cell-type specific and temporal expression analysis revealed that NFIB is primarily expressed in the radial glial subclass of neural stem/progenitors and in corticofugal projection neurons throughout corticogenesis. Using a loss of function approach, we compared neocortical development of wildtype (NfiB+/+) and NfiB-deficient (NfiB−/−) mice to identify the role of NfiB. Results revealed that NfiB is required for proper generation of outer radial glia and basal progenitors during late corticogenesis. Loss of these neural progenitor populations led to defects in late-stage neurogenesis and cortical lamination. Specifically, there was an increase in corticofugal–like neurons generated after the expected wave of corticofugal neurogenesis. Additionally, there were defects in neuronal migration and an overall reduction in upper layer thickness. We showed that NFIB is also required for axonal outgrowth of corticofugal projection neurons, such that NfiB−/− brains displayed a severe loss of axon projections to thalamic and subcerebral targets compared to wildtype controls. Furthermore, genome-wide, RNA-sequencing analysis revealed downstream effectors of NFIB, including genes involved in cell-cycle progression, and neuronal differentiation and migration. Together, these data indicate the broad, yet critical roles for NfiB during the development and organization of the mouse cerebral cortex.. |
