title: NFIA controls telencephalic progenitor cell differentiation through repression of the Notch effector Hes1.
abstract: The balance between self-renewal and differentiation of neural progenitor cells is an absolute requirement for the correct formation of the nervous system. Much is known about both the pathways involved in progenitor cell self-renewal, such as Notch signaling, and the expression of genes that initiate progenitor differentiation. However, whether these fundamental processes are mechanistically linked, and specifically how repression of progenitor self-renewal pathways occurs, is poorly understood. Nuclear factor I A (Nfia), a gene known to regulate spinal cord and neocortical development, has recently been implicated as acting downstream of Notch to initiate the expression of astrocyte-specific genes within the cortex. Here we demonstrate that, in addition to activating the expression of astrocyte-specific genes, Nfia also downregulates the activity of the Notch signaling pathway via repression of the key Notch effector Hes1. These data provide a significant conceptual advance in our understanding of neural progenitor differentiation, revealing that a single transcription factor can control both the activation of differentiation genes and the repression of the self-renewal genes, thereby acting as a pivotal regulator of the balance between progenitor and differentiated cell states.
authors.affiliation: Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Piper
authors.forename: Guy
authors.initials: G
authors.lastname: Barry
authors.forename: John
authors.initials: J
authors.lastname: Hawkins
authors.forename: Sharon
authors.initials: S
authors.lastname: Mason
authors.forename: Charlotta
authors.initials: C
authors.lastname: Lindwall
authors.forename: Erica
authors.initials: E
authors.lastname: Little
authors.forename: Anindita
authors.initials: A
authors.lastname: Sarkar
authors.forename: Aaron G
authors.initials: AG
authors.lastname: Smith
authors.forename: Randal X
authors.initials: RX
authors.lastname: Moldrich
authors.forename: Glen M
authors.initials: GM
authors.lastname: Boyle
authors.forename: Shubha
authors.initials: S
authors.lastname: Tole
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gronostajski
authors.forename: Timothy L
authors.initials: TL
authors.lastname: Bailey
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Richards
mesh_terms: D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D002454:Cell Differentiation / Q000235:genetics*; D002552:Cerebral Ventricles / Q000166:cytology / Q000196:embryology; D047369:Chromatin Immunoprecipitation / Q000379:methods; D024202:Electrophoretic Mobility Shift Assay / Q000379:methods; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D006624:Hippocampus / Q000166:cytology / Q000254:growth & development; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046228:Microarray Analysis / Q000379:methods; D009154:Mutation / Q000235:genetics; D051839:NFI Transcription Factors / Q000172:deficiency / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D050816:Octamer Transcription Factor-6 / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D018092:Kainic Acid Receptors / Q000235:genetics / Q000378:metabolism; D013234:Stem Cells / Q000502:physiology*; D013687:Telencephalon / Q000166:cytology* / Q000196:embryology; D000072056:Transcription Factor HES-1; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000098551:Prospero-Related Homeobox 1 Protein
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D001973:Bromodeoxyuridine; D018398:Homeodomain Proteins; D051839:NFI Transcription Factors; D009419:Nerve Tissue Proteins; D050816:Octamer Transcription Factor-6; D018092:Kainic Acid Receptors; D000072056:Transcription Factor HES-1; D025521:Tumor Suppressor Proteins; D000098551:Prospero-Related Homeobox 1 Protein; C534874:Grik4 protein, mouse; C489734:Hes1 protein, mouse; C497646:Nfia protein, mouse; C494180:Pou3f1 protein, mouse