Nuclear factor one X regulates the development of multiple cellular populations in the postnatal cerebellum

Piper, Michael; Harris, Lachlan; Barry, Guy; Heng, Yee Hsieh Evelyn; Plachez, Céline; Gronostajski, Richard M.; Richards, Linda J.

doi:10.1002/cne.22721

Cited by 51 publications

(64 citation statements)

References 57 publications

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“…Mice lacking Nfix exhibit markedly reduced numbers of astrocytes throughout the embryonic cerebral cortex and cerebellum (Piper et al, 2011;Heng et al, 2014). In addition to promoting astrocyte lineage progression, individual Nfi knockout mice also exhibit elevated numbers of progenitor cells and delayed expression of neuronal markers within the ammonic neuroepithelium of the presumptive hippocampus during embryonic development (Piper et al, 2010(Piper et al, , 2014Heng et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of intermediate progenitor cell generation during hippocampal development

et al. 2016

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During forebrain development, radial glia generate neurons through the production of intermediate progenitor cells (IPCs). The production of IPCs is a central tenet underlying the generation of the appropriate number of cortical neurons, but the transcriptional logic underpinning this process remains poorly defined. Here, we examined IPC production using mice lacking the transcription factor nuclear factor I/X (Nfix). We show that Nfix deficiency delays IPC production and prolongs the neurogenic window, resulting in an increased number of neurons in the postnatal forebrain. Loss of additional Nfi alleles (Nfib) resulted in a severe delay in IPC generation while, conversely, overexpression of NFIX led to precocious IPC generation. Mechanistically, analyses of microarray and ChIP-seq datasets, coupled with the investigation of spindle orientation during radial glial cell division, revealed that NFIX promotes the generation of IPCs via the transcriptional upregulation of inscuteable (Insc). These data thereby provide novel insights into the mechanisms controlling the timely transition of radial glia into IPCs during forebrain development.

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Section: Introductionmentioning

confidence: 99%

Transcriptional regulation of intermediate progenitor cell generation during hippocampal development

et al. 2016

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“…Notably, NFI-X knock-out mice exhibit defects in proliferation and migration of the subventricular zone progenitor cells (10). Although neuronal precursors are strongly affected in these mice, the absence of NFI-X also delays differentiation of mature glia (44). Moreover, both NFI-A and NFI-B govern tangential neuronal migration by regulating expression of ephrin-B1 and N-cadherin, which are cell adhesion molecules (45).…”

Section: Discussionmentioning

confidence: 99%

A Complex of Nuclear Factor I-X3 and STAT3 Regulates Astrocyte and Glioma Migration through the Secreted Glycoprotein YKL-40

Singh

Bhardwaj

Wilczynska

et al. 2011

Journal of Biological Chemistry

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Nuclear factor I-X3 (NFI-X3) is a newly identified splice variant of NFI-X that regulates expression of several astrocyte-specific markers, such as glial fibrillary acidic protein. Here, we identified a set of genes regulated by NFI-X3 that includes a gene encoding a secreted glycoprotein YKL-40. Although YKL-40 expression is up-regulated in glioblastoma multiforme, its regulation and functions in nontransformed cells of the central nervous system are widely unexplored. We find that expression of YKL-40 is activated during brain development and also differentiation of neural progenitors into astrocytes in vitro. Furthermore, YKL-40 is a migration factor for primary astrocytes, and its expression is controlled by both NFI-X3 and STAT3, which are known regulators of gliogenesis. Knockdown of NFI-X3 and STAT3 significantly reduced YKL-40 expression in astrocytes, whereas overexpression of NFI-X3 dramatically enhanced YKL-40 expression in glioma cells. Activation of STAT3 by oncostatin M induced YKL-40 expression in astrocytes, whereas expression of a dominant-negative STAT3 had a suppressive effect. Mechanistically, NFI-X3 and STAT3 form a complex that binds to weak regulatory elements in the YKL-40 promoter and activates transcription. We propose that NFI-X3 and STAT3 control the migration of differentiating astrocytes as well as migration and invasion of glioma cells via regulating YKL-40 expression.Astrocytes, the most abundant CNS cells, are critical for many functions of normal and pathological brains (1, 2). Generation and differentiation of astrocytes from neural progenitors is controlled by activation of the JAK-STAT3, BMP-SMAD, and Notch-HES pathways in vivo (3, 4) and promoted by cytokines of the IL-6 family that activate STAT3 in vitro (5, 6). In addition to these pathways, evolutionarily conserved NFI 3 transcription factors, consisting of NFI-A, -B, -C, and -X, regulate astrocyte differentiation (7,8). NFIs are expressed in overlapping patterns during embryogenesis, with high expression levels of NFI-A, -B, and -X found in the developing neocortex (9, 10). Consequently, Nfia, Nfib, and Nfix knock-out mice show severe brain anatomical defects, including agenesis of corpus callosum (9, 10), whereas NPs from Nfix knock-out mice show defects in proliferation and migration (9, 10). NFI-A and -B control gliogenesis in chick embryonic spinal cord (7), whereas NFI-X and -C regulate the expression of late astrocyte markers during the differentiation of human NPs in vitro (7,8). Expression of NFI-A is induced by Notch signaling in NP and leads to the demethylation of astrocyte-specific genes (11), as well as down-regulation of Notch signaling via repression of Notch effector Hes1 (12). Each of the NFI transcripts undergoes alternative splicing, generating as many as nine different NFI splice variants (13), likely possessing distinctive functions. We have recently characterized a novel human NFI-X3 splice variant, which is a potent activator of gene expression in astrocytes (14). NFI-X3 contains a unique transcri...

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“…The cerebellar phenotype of Nfia null mice is consistent with in vitro and ex vivo findings, with P17 Nfia-deficient mice exhibiting shortened and disorientated parallel fibres and retarded migration of GNP cells within the cerebellum . Similarly, delayed GNP maturation was also observed in Nfix-deficient mice; however this was not thought to be a consequence of a migratory defect of GNPs per se, but rather an overall delay in the development and differentiation of GNPs (Piper et al, 2011). Together these data strongly implicate NFI transcription factors in regulating various aspects of GNP maturation, including the switch from an immature, proliferating GNP to a post-mitotic GNP that has commenced its migration.…”

Section: Nfis Promote Cerebellar Granule Neuron Developmentmentioning

confidence: 73%

“…For example, in the developing CNS inactivation of Nfia, Nfib or Nfix alone, is sufficient to render severe forebrain defects (Shu et al, 2003;Steele-Perkins et al, 2005;Campbell et al, 2008). Likewise in the developing cerebellum, NFIA, NFIB and NFIX are alone functionally required for normal development (Steele-Perkins et al, 2005;Wang et al, 2010;Piper et al, 2011). Interestingly however, these null lines still exhibit broadly similar phenotypes.…”

Section: Genetic Redundancy Of Nfis During Developmentmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The function of NFIX during developmental and adult neurogenesis

Harris¹

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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 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-

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Nuclear factor one X regulates the development of multiple cellular populations in the postnatal cerebellum

Cited by 51 publications

References 57 publications

Transcriptional regulation of intermediate progenitor cell generation during hippocampal development

Transcriptional regulation of intermediate progenitor cell generation during hippocampal development

A Complex of Nuclear Factor I-X3 and STAT3 Regulates Astrocyte and Glioma Migration through the Secreted Glycoprotein YKL-40

The function of NFIX during developmental and adult neurogenesis

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