A positive autoregulatory loop of Jak-STAT signaling controls the onset of astrogliogenesis.
During development of the CNS, neurons and glia are generated in a sequential manner. The mechanism underlying the later onset of gliogenesis is poorly understood, although the cytokine-induced Jak-STAT pathway has been postulated to regulate astrogliogenesis. Here, we report that the overall activity of Jak-STAT signaling is dynamically regulated in mouse cortical germinal zone during development. As such, activated STAT1/3 and STAT-mediated transcription are negligible at early, neurogenic stages, when neurogenic factors are highly expressed. At later, gliogenic periods, decreased expression of neurogenic factors causes robust elevation of STAT activity. Our data demonstrate a positive autoregulatory loop whereby STAT1/3 directly induces the expression of various components of the Jak-STAT pathway to strengthen STAT signaling and trigger astrogliogenesis. Forced activation of Jak-STAT signaling leads to precocious astrogliogenesis, and inhibition of this pathway blocks astrocyte differentiation. These observations suggest that autoregulation of the Jak-STAT pathway controls the onset of astrogliogenesis.
He
Fei
F
Department of Molecular & Medical Pharmacology, Neuropsychiatric Institute, University of California Los Angeles, Los Angeles, California 90024, USA.
Ge
Weihong
W
Martinowich
Keri
K
Becker-Catania
Sara
S
Coskun
Volkan
V
Zhu
Wenyu
W
Wu
Hao
H
Castro
Diogo
D
Guillemot
Francois
F
Fan
Guoping
G
de Vellis
Jean
J
Sun
Yi E
YE
D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000201:enzymology*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002490:Central Nervous System / Q000166:cytology / Q000196:embryology* / Q000201:enzymology*; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005809:Genes, Regulator / Q000502:physiology; D006706:Homeostasis / Q000502:physiology; D053613:Janus Kinase 1; D051379:Mice; D008807:Mice, Inbred BALB C; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction / Q000502:physiology; D013234:Stem Cells / Q000166:cytology / Q000201:enzymology*; D015534:Trans-Activators / Q000378:metabolism*; D015533:Transcriptional Activation / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
D004268:DNA-Binding Proteins; D009414:Nerve Growth Factors; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1