NFIX Regulates Proliferation and Migration Within the Murine SVZ Neurogenic Niche

Heng, Yee Hsieh Evelyn; Zhou, Bo; Harris, Lachlan; Harvey, Tracey J.; Smith, Aaron G.; Horne, Elise; Martynoga, Ben; Andersen, Jimena; Achimastou, Angeliki; Cato, Kathleen; Richards, Linda J.; Gronostajski, Richard M.; Yeo, Giles S.H.; Guillemot, François; Bailey, Timothy L.; Piper, Michael

doi:10.1093/cercor/bhu253

Cited by 47 publications

(62 citation statements)

References 66 publications

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“…In addition, the migration of SVZ-derived neuroblasts to the olfactory bulb was impaired in mutant mice, suggesting that NFIX regulates this process in vivo. These findings were recently published in the prestigious international journal Cerebral Cortex (Heng YHE et al, 2014). Collectively, this work highlights the important role played by NFIX in the biology of the SVZ, and reveals that NFIX mediates multiple processes within this region of the brain.…”

supporting

confidence: 63%

“…Instead, most of our understanding of how NFI transcription factors regulate cortical development had been obtained by studying mice lacking either Nfia or Nfib . My thesis has provided a number of conceptual advances to the field, providing significant insights into the role of NFIX as a mediator of neural stem cell biology within the nascent hippocampus ) and the SVZ (Heng YHE et al, 2014) of the postnatal lateral ventricles. Moreover, I contributed to a recent study revealing NFIX is also important for the normal formation of the cerebellum during the postnatal period in mice , and a further study demonstrating that NFIX is important for hippocampal-specific learning and memory within adult mice .…”

Section: Chapter 6 Discussionmentioning

confidence: 99%

“…With regards to the data presented in this chapter, the findings have been incorporated into a manuscript along with the description of the SVZ phenotype of Nfix -/-mice, which has recently been published in Cerebral Cortex (Heng YHE et al 2014 - …”

Section: Aims Of Chaptermentioning

confidence: 99%

“…With regards to the data presented in this chapter, the findings have been incorporated into a manuscript along with the expression of NFIX within the SVZ, RMS and olfactory bulb mice, which has recently published in Cerebral Cortex (Heng YHE et al 2014). In which, I revealed that NFIX acts in a pleiotropic fashion within the postnatal SVZ, regulating neural progenitor cell proliferation, while also mediating the migration of SVZ-derived neuroblasts to the olfactory bulb.…”

Section: Aims Of Chaptermentioning

confidence: 99%

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

Heng¹

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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....

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supporting

confidence: 63%

Section: Chapter 6 Discussionmentioning

confidence: 99%

Section: Aims Of Chaptermentioning

confidence: 99%

Section: Aims Of Chaptermentioning

confidence: 99%

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

Heng¹

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“…Remarkably, several of these additional identified genes are known to be involved in the process of neuronal migration, including Dync1h1, a dynein motor protein, and Nrcam, a neuronal cell-adhesion protein associated with psychiatric disorders such as autism (27)(28)(29). The expression of Nfia, a family member of Nfix, which has been shown to be involved in regulating the rostral migratory stream of SVZ-derived neuroblasts (30), was, like Plxna4, significantly decreased upon siRNA-mediated knockdown of FoxO6.…”

Section: Discussionmentioning

confidence: 99%

FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development

Paap

Oosterbroek

Wagemans

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The forkhead transcription factor FoxO6 is prominently expressed during development of the murine neocortex. However, its function in cortical development is as yet unknown. We now demonstrate that cortical development is altered in FoxO6 +/− and FoxO6 −/− mice, showing migrating neurons halted in the intermediate zone. Using a FoxO6-directed siRNA approach, we substantiate the requirement of FoxO6 for a correct radial migration in the developing neocortex. Subsequent genome-wide transcriptome analysis reveals altered expression of genes involved in cell adhesion, axon guidance, and gliogenesis upon silencing of FoxO6. We then show that FoxO6 binds to DAF-16-binding elements in the Plexin A4 (Plxna4) promoter region and affects Plxna4 expression. Finally, ectopic Plxna4 expression restores radial migration in FoxO6 +/− and siRNA-mediated knockdown models. In conclusion, the presented data provide insights into the molecular mechanisms whereby transcriptional programs drive cortical development.

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Differential neuronal and glial expression of nuclear factor I proteins in the cerebral cortex of adult mice

Chen

Harris

Lim

et al. 2017

J of Comparative Neurology

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The nuclear factor I (NFI) family of transcription factors plays an important role in the development of the cerebral cortex in humans and mice. Disruption of nuclear factor IA (NFIA), nuclear factor IB (NFIB), or nuclear factor IX (NFIX) results in abnormal development of the corpus callosum, lateral ventricles, and hippocampus. However, the expression or function of these genes has not been examined in detail in the adult brain, and the cell type-specific expression of NFIA, NFIB, and NFIX is currently unknown. Here, we demonstrate that the expression of each NFI protein shows a distinct laminar pattern in the adult mouse neocortex and that their cell type-specific expression differs depending on the family member. NFIA expression was more frequently observed in astrocytes and oligodendroglia, whereas NFIB expression was predominantly localized to astrocytes and neurons. NFIX expression was most commonly observed in neurons. The NFI proteins were equally distributed within microglia, and the ependymal cells lining the ventricles of the brain expressed all three proteins. In the hippocampus, the NFI proteins were expressed during all stages of neural stem cell differentiation in the dentate gyrus, with higher expression intensity in neuroblast cells as compared to quiescent stem cells and mature granule neurons. These findings suggest that the NFI proteins may play distinct roles in cell lineage specification or maintenance, and establish the basis for further investigation of their function in the adult brain and their emerging role in disease.

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NFIX Regulates Proliferation and Migration Within the Murine SVZ Neurogenic Niche

Cited by 47 publications

References 66 publications

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

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

FoxO6 affects Plxna4-mediated neuronal migration during mouse cortical development

Differential neuronal and glial expression of nuclear factor I proteins in the cerebral cortex of adult mice

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