Notch signaling promotes astrogliogenesis via direct CSL-mediated glial gene activation.
In the developing central nervous system (CNS), Notch signaling preserves progenitor pools and inhibits neurogenesis and oligodendroglial differentiation. It has recently been postulated that Notch instructively drives astrocyte differentiation. Whether the role of Notch signaling in promoting astroglial differentiation is permissive or instructive has been debated. We report here that the astrogliogenic role of Notch is in part mediated by direct binding of the Notch intracellular domain to the CSL DNA binding protein, forming a transcriptional activation complex onto the astrocyte marker gene, glial fibrillary acidic protein (GFAP). In addition, we found that, in CSL-/- neural stem cell cultures, astrocyte differentiation was delayed but continued at a normal rate once initiated, suggesting that CSL is involved in regulating the onset of astrogliogenesis. Importantly, although the classical CSL-dependent Notch signaling pathway is intact and able to activate the Notch canonical target promoter during the neurogenic phase, it is unable to activate the GFAP promoter during neurogenesis. Therefore, the effect of Notch signaling on target genes is influenced by cellular context in regulation of neurogenesis and gliogenesis.
Department of Psychiatry and Behavioral Sciences, University of California at Los Angeles, School of Medicine, Los Angeles, California 90024, USA.
Weihong
W
Ge
Keri
K
Martinowich
Xiangbing
X
Wu
Fei
F
He
Alison
A
Miyamoto
Guoping
G
Fan
Gerry
G
Weinmaster
Yi Eve
YE
Sun
D000818:Animals; D001253:Astrocytes / Q000166:cytology* / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004268:DNA-Binding Proteins / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental; D005904:Glial Fibrillary Acidic Protein / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016296:Mutagenesis / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; D015398:Signal Transduction / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology* / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism; D015533:Transcriptional Activation / Q000502:physiology
D004268:DNA-Binding Proteins; D005904:Glial Fibrillary Acidic Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; C494088:Stat3 protein, rat; D015534:Trans-Activators; C064045:delta protein; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; C507906:Jak1 protein, rat; D053613:Janus Kinase 1