NFIX regulates neural progenitor cell differentiation during hippocampal morphogenesis

Heng, Yee Hsieh Evelyn, McLeay, Robert C., Harvey, Tracey J., Smith, Aaron G., Barry, Guy, Cato, Kathleen, Plachez, Celine, Little, Erica, Mason, Sharon, Dixon, Chantelle, Gronostajski, Richard M., Bailey, Timothy L., Richards, Linda J. and Piper, Michael (2014) NFIX regulates neural progenitor cell differentiation during hippocampal morphogenesis. Cerebral Cortex, 24 1: 261-279. doi:10.1093/cercor/bhs307

Author Heng, Yee Hsieh Evelyn
McLeay, Robert C.
Harvey, Tracey J.
Smith, Aaron G.
Barry, Guy
Cato, Kathleen
Plachez, Celine
Little, Erica
Mason, Sharon
Dixon, Chantelle
Gronostajski, Richard M.
Bailey, Timothy L.
Richards, Linda J.
Piper, Michael
Title NFIX regulates neural progenitor cell differentiation during hippocampal morphogenesis
Journal name Cerebral Cortex   Check publisher's open access policy
ISSN 1460-2199
ISBN 0-12-364553-0
Publication date 2014-01-01
Year available 1994
Sub-type Article (original research)
DOI 10.1093/cercor/bhs307
Open Access Status DOI
Volume 24
Issue 1
Start page 261
End page 279
Total pages 19
Place of publication Oxford, United Kingdom
Publisher Oxford University Press
Language eng
Subject 2805 Cognitive Neuroscience
2804 Cellular and Molecular Neuroscience
Abstract 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.
Formatted abstract
Neural progenitor cells have the ability to give rise to neurons and glia in the embryonic, postnatal and adult brain. During development, the program regulating whether these cells divide and self-renew or exit the cell cycle and differentiate is tightly controlled, and imbalances to the normal trajectory of this process can lead to severe functional consequences. However, our understanding of the molecular regulation of these fundamental events remains limited. Moreover, processes underpinning development of the postnatal neurogenic niches within the cortex remain poorly defined. Here, we demonstrate that Nuclear factor one X (NFIX) is expressed by neural progenitor cells within the embryonic hippocampus, and that progenitor cell differentiation is delayed within Nfix−/− mice. Moreover, we reveal that the morphology of the dentate gyrus in postnatal Nfix−/− mice is abnormal, with fewer subgranular zone neural progenitor cells being generated in the absence of this transcription factor. Mechanistically, we demonstrate that the progenitor cell maintenance factor Sry-related HMG box 9 (SOX9) is upregulated in the hippocampus of Nfix−/− mice and demonstrate that NFIX can repress Sox9 promoter-driven transcription. Collectively, our findings demonstrate that NFIX plays a central role in hippocampal morphogenesis, regulating the formation of neuronal and glial populations within this structure.
Keyword Glia
Glial fibrillary acidic protein
Neural progenitor cell
Nuclear factor one X
Q-Index Code C1
Q-Index Status Confirmed Code
Grant ID R01 HL080624
Institutional Status UQ
Additional Notes First published online: October 4, 2012

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Created: Thu, 08 Nov 2012, 00:41:56 EST by Debra McMurtrie on behalf of Queensland Brain Institute