Transcription factor RBP-J-mediated signaling represses the differentiation of neural stem cells into intermediate neural progenitors.
Notch signaling is critical for multiple aspects of neurogenesis, but how it regulates the proliferation and differentiation of neural stem cells (NSCs) and intermediate neural progenitors (INPs) has not been well elucidated, especially in vivo. In this study, we conditionally ablated the transcription factor RBP-J, which mediates signaling from all four mammalian Notch receptors, in the basal forebrain and ventral midbrain using the RBP-J-floxed mouse and a newly established Nestin-Cre mouse. We found that at early stage of neurogenesis (E11.5), the frequency of neurospheres increased significantly in the RBP-J-inactivated regions. The majority of the RBP-J deficient neurospheres were composed of INPs, suggesting the precocious differentiation of NSCs into INPs. Meanwhile, neuronal differentiation was reduced in the same regions at E11.5, inconsistent with the precocious differentiation phenotype in most Notch-related mutants. At late neurogenic stages (E17.5 and neonatal), as expected from precociously exhausted NSC pool, neurosphere frequency and NSCs decreased in the RBP-J-ablated regions, accompanied by a significant increase of both neurons and glial cells. These results indicated that the RBP-J-mediated signaling might inhibit the differentiation of NSCs into INPs and support the generation of certain early born neurons at early neurogenic stages.
Gao
Fang
F
Department of Medical Genetics and Developmental Biology, Fourth Military Medical University, Chang-Le Xi Street #17, Xian 710032, China.
Zhang
Qi
Q
Zheng
Min-Hua
MH
Liu
Hui-Ling
HL
Hu
Yi-Yang
YY
Zhang
Ping
P
Zhang
Zheng-Ping
ZP
Qin
Hong-Yan
HY
Feng
Lei
L
Wang
Li
L
Han
Hua
H
Ju
Gong
G
D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000033:anatomy & histology / Q000502:physiology; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D064231:Nestin; D055495:Neurogenesis / Q000502:physiology; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D051880:Receptors, Notch / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D019076:Transgenes
D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007381:Intermediate Filament Proteins; C577484:NES protein, human; D009419:Nerve Tissue Proteins; C577485:Nes protein, mouse; D064231:Nestin; C497571:Rbpj protein, mouse; D051880:Receptors, Notch