The role of Nfix in the development of the embryonic and postnatal cerebral cortex

Abstract

Neurogenesis is an intricate process that is essential for the proper formation of the central nervous system (CNS) during development, which continues into postnatal ages and throughout adulthood within two restricted regions of the rodent brain: the subgranular zone (SGZ) of the hippocampal dentate gyrus and the subventricular zone (SVZ) lining the lateral ventricles. This process relies on a series of events, including progenitor cell proliferation and differentiation, and the subsequent migration of newborn neurons to their ultimate destination within the brain. These events are tightly orchestrated by multiple different transcription factors in a spatially and temporally specific manner. Alteration in any of these events can lead to cognitive, motor and intellectual disabilities, which is why it is critically important to understand how neural progenitor cell proliferation and differentiation is regulated.This thesis focuses on the role of Nuclear factor one X (NFIX) in regulating neural progenitor cell biology within the developing and postnatal SGZ and SVZ. NFIX belongs to a group of site-specific transcription factors known as the Nuclear factor one (NFI) family. Previous studies have shown that NFI proteins play multiple roles during development of the CNS, including axon guidance, neuronal migration, progenitor cell differentiation, gliogenesis and neurogenesis . However, much of the focus on this family with relation to neural development has been centred on NFIA and NFIB, as knockout mice for these genes were generated first (das Neves L et al. 1999;Grunder A et al. 2002).However, both Nfia -/-and Nfib -/-mice die in the early perinatal period, which precludes the use of these mice as models to investigate genesis of the postnatal and adult brain neurogenic niches.iii Although the role of NFIX in cortical development has been less intensively investigated, Nfix -/-mice survive postnatally , making this strain a valuable model in which to investigate the transcriptional control of stem cell biology within the SVZ and SGZ. Preliminary data has revealed that NFIX is expressed by neural progenitor cells within the CNS, and that mice lacking this gene possess abnormal phenotypes within the hippocampus and the SVZ postnatally . However, these preliminary findings did not investigate the cellular or molecular mechanisms by which NFIX exert its effects. As such, the goal of this thesis was to expand these findings, and to elucidate the role of NFIX during the development of the hippocampus and the SVZ, and, moreover, to identify the downstream targets via which this transcription factor regulates progenitor cell proliferation and differentiation within these regions. Furthermore, this thesis also focussed on the role of NFIX in the olfactory system, including the olfactory bulb, rostral migratory stream (RMS) and the SVZ during development, postnatally and within the adult. Firstly, I extensively mapped the expression of NFIX within these areas at a cell-type specific level using confocal microscopy....