The role of nuclear factor one (NFI) in cortical development

Mason, Sharon Anne (2012). The role of nuclear factor one (NFI) in cortical development PhD Thesis, Queensland Brain Institute, The University of Queensland.

       
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Author Mason, Sharon Anne
Thesis Title The role of nuclear factor one (NFI) in cortical development
School, Centre or Institute Queensland Brain Institute
Institution The University of Queensland
Publication date 2012
Thesis type PhD Thesis
Supervisor Linda Richards
Michael Piper
Total pages 390
Total colour pages 64
Total black and white pages 326
Language eng
Subjects 06 Biological Sciences
0601 Biochemistry and Cell Biology
060103 Cell Development, Proliferation and Death
Formatted abstract Understanding key cellular processes that construct the architectonic plan for the cortex, and thereby the foundation for early brain wiring events, is critical to assist in our understanding of numerous human congenital syndromes. These syndromes have defects in important basic cellular processes including neuron production, neuronal migration and neuronal maturation. These cellular processes have similarities in both human and mouse. As a result of this, and the ease of genetic manipulation in the mouse, this model system is suitable to address many questions in mammalian corticogenesis. Members of the Nuclear Factor One (NFI) transcription factor family comprising NFIA, NFIB, NFIC and NFIX have been identified as being highly expressed in the developing mouse brain. Within the mouse central nervous system (CNS), NFI transcription factors regulate the development of numerous CNS systems, including the spinal cord, basilar pons and hippocampus through regulating the differentiation of progenitor cells into neurons or glia. Additionally, NFI controls the post-mitotic development of cerebellar granule neurons.

In this Thesis the role of the NFI gene family in the development of the mouse neocortex is investigated. The precise spatial and temporal protein expression of the NFIB family member during corticogenesis is described, with NFIB detected in both progenitor and neuronal populations from early stages of neurogenesis. Given the expression pattern of NFIB, a main hypothesis of this thesis was that NFI may be involved in directing early neurogensis events within the neocortex, in addition to a role in the post-mitotic development of the deep layer corticofugal neurons. The cortical phenotype of the Nfib knockout mouse, compared to wildtype and Nfib heterozygous littermates was therefore characterised. This analysis demonstrated that NFIB is needed for the differentiation of basal progenitors. Defects in the timing of basal progenitor formation leads to delays in cortical plate lamination and axon outgrowth in the nascent cortex, including a disruption in the formation of the corticofugal and thalamocortical tracts. The defects are dependent upon the amount of NFIB in the system, as Nfib heterozygous mice demonstrate an intermediate phenotype.

Given the early defects in neurogenesis in the Nfib-deficient mice, the radial glial population of the neocortex was characterised. Deficiencies were identified in radial glial differentiation. In correlation with this data, it was also shown that over-expression of Nfib into the neocortex in vivo caused accelerated radial glial cell differentiation. Furthermore, microarray gene expression profiling in Nfib knockout cortices compared to wildtype revealed that genes in the notch pathway and progenitor cell maintenance, cell cycle regulators, were up-regulated in the absence of NFIB. Additionally, molecules involved in axon outgrowth and basal progenitor formation were down-regulated in the Nfib-deficient mice compared to wildtype.

Finally, NFIB was expressed in a high caudomedial to low rostrolateral gradient within the pseudostratified ventricular epithelium, and in the Nfib knockout mice, the lateromedial cortical maturation gradient was delayed, demonstrating that NFIB contributes to the cortical maturation gradient in normal development.

Collectively, the expression, cellular and molecular data suggests that NFIB is required to direct the neurogenic competence and maturation of the radial glial population that constitute the germinal zone of the cortical wall and in the absence of NFIB, the radial glial cell population fails to produce neurons or neurogenic progenitors at the appropriate time in corticogenesis. This Thesis highlights NFIB as a key regulator of radial glial cell development and the analysis of NFIB mis-regulation is therefore of interest to pursue within the context of human congenital syndromes.
Keyword Nuclear factor one
Neocortex
Neurogenesis
Differentiation
Corticofugal
Radial glia
Basal progenitors

 
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Created: Thu, 27 Sep 2012, 15:31:09 EST by Sharon Mason on behalf of Scholarly Publishing and Digitisation Service