NFIA controls telencephalic progenitor cell differentiation through repression of the Notch effector Hes1.
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.
Piper
Michael
M
Queensland Brain Institute, The University of Queensland, Brisbane, Australia.
Barry
Guy
G
Hawkins
John
J
Mason
Sharon
S
Lindwall
Charlotta
C
Little
Erica
E
Sarkar
Anindita
A
Smith
Aaron G
AG
Moldrich
Randal X
RX
Boyle
Glen M
GM
Tole
Shubha
S
Gronostajski
Richard M
RM
Bailey
Timothy L
TL
Richards
Linda J
LJ
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
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