Sip1 regulates sequential fate decisions by feedback signaling from postmitotic neurons to progenitors.
The fate of cortical progenitors, which progressively generate neurons and glial cells during development, is determined by temporally and spatially regulated signaling mechanisms. We found that the transcription factor Sip1 (Zfhx1b), which is produced at high levels in postmitotic neocortical neurons, regulates progenitor fate non-cell autonomously. Conditional deletion of Sip1 in young neurons induced premature production of upper-layer neurons at the expense of deep layers, precocious and increased generation of glial precursors, and enhanced postnatal astrocytogenesis. The premature upper-layer generation coincided with overexpression of the neurotrophin-3 (Ntf3) gene and upregulation of fibroblast growth factor 9 (Fgf9) gene expression preceded precocious gliogenesis. Exogenous application of Fgf9 to mouse cortical slices induced excessive generation of glial precursors in the germinal zone. Our data suggest that Sip1 restrains the production of signaling factors in postmitotic neurons that feed back to progenitors to regulate the timing of cell fate switch and the number of neurons and glial cells throughout corticogenesis.
Laboratory of Molecular Biology (Celgen), Centre for Human Genetics, KULeuven, Leuven, Belgium.
Eve
E
Seuntjens
Anjana
A
Nityanandam
Amaya
A
Miquelajauregui
Joke
J
Debruyn
Agata
A
Stryjewska
Sandra
S
Goebbels
Klaus-Armin
KA
Nave
Danny
D
Huylebroeck
Victor
V
Tarabykin
D000818:Animals; D001973:Bromodeoxyuridine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D049109:Cell Proliferation / Q000187:drug effects; D004622:Embryo, Mammalian; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology*; D051525:Fibroblast Growth Factor 9 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D019579:Neocortex / Q000166:cytology* / Q000196:embryology; D009419:Nerve Tissue Proteins / Q000172:deficiency / Q000502:physiology*; D055495:Neurogenesis / Q000502:physiology; D009457:Neuroglia / Q000502:physiology; D009474:Neurons / Q000502:physiology*; D020933:Neurotrophin 3 / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000187:drug effects / Q000502:physiology*; D013997:Time Factors
D051525:Fibroblast Growth Factor 9; D009419:Nerve Tissue Proteins; D020933:Neurotrophin 3; D012333:RNA, Messenger; C491561:Sip1 protein, mouse; D001973:Bromodeoxyuridine