The function of NFIX during developmental and adult neurogenesis

Abstract

Understanding the transcription factor proteins that control the biology of neural stem cells during embryogenesis provides insight into brain development as well as neurodevelopmental disorders. Likewise, studying the function of transcription factors in adult neural stem cells allows us to appreciate the dynamics of these cells and their contribution to normal cognitive function. It also provides a knowledge base so as to one day harness the activity of adult neural stem cells to treat degenerative conditions of the nervous system. One family of transcription factors key to brain development are the Nuclear Factor Ones (NFIs). Comprised of four members in mammals (NFIA, NFIB, NFIC and NFIX) these proteins promote both neuronal and glial differentiation during mouse forebrain development, and in general, appear to have a highly similar function. This thesis addressed two outstanding questions regarding the function of one these proteins, NFIX, in mouse neural stem cell biology. The first question concerned refining our understanding of NFIX function during forebrain development by determining, which stage of neuron differentiation, from a stem cell to a mature neuron, is controlled by NFIX? I answered this question by studying early changes in progenitor populations in loss-of-function mice, revealing that NFIX promotes the production of intermediate neuronal progenitors by directing stem cells to divide in an asymmetric manner. Mechanistically, this was because NFIX, and NFIA/B activated the expression of the spindle regulator Inscuteable, which changes cleavage plane orientations to direct an intermediate neuronal progenitor cell fate. The significance of this finding to neurodevelopmental disorders caused by de novo NFIX mutations is discussed. The second question I addressed in this thesis, was that if NFI proteins are so important for regulating neural stem cell biology during brain development, then do they also regulate adult neural stem cell biology? I addressed this question by breeding inducible, conditional mice to allow for deletion of Nfix from adult hippocampal neural stem cells and separately, immature neurons. I found that NFIX is essential for adult-borne neuron differentiation, so that in the absence of NFIX, mature neurons are not generated and behavioural deficits ensue. Mechanistically, we found that NFIX is essential for primary dendrite formation, and that without NFIX a proportion of adult hippocampal progenitors switch fate to become oligodendrocytes or aberrantly express increased levels of oligodendrocyte mRNA. In addition to demonstrating the absolute requirement of the NFIX protein for the generation of adult-borne neurons, these findings reveal the surprising tri-potency of adult hippocampal progenitor cells. This information may prove useful when considering strategies to harness the endogenous neural stem cell activity of the adult brain to treat demyelination disorders.