RP58 controls neuron and astrocyte differentiation by downregulating the expression of Id1-4 genes in the developing cortex

• Published in: The EMBO journal 2012-03, Vol.31 (5), p.1190-1202
• Main Authors: Hirai, Shinobu, Miwa, Akiko, Ohtaka-Maruyama, Chiaki, Kasai, Masataka, Okabe, Shigeo, Hata, Yutaka, Okado, Haruo
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes - cytology; Cell cycle; cell cycle control; Cell Differentiation; Cerebral Cortex - cytology; Cerebral Cortex - embryology; cortical development; cyclin-dependent kinase inhibitor; EMBO11; EMBO27; fate of NSCs; Gene Expression; Gene Expression Regulation; Gene Knockdown Techniques; Inhibitor of Differentiation Proteins - genetics; Inhibitor of Differentiation Proteins - metabolism; Kinases; Mice; Mice, Knockout; Neurons; Neurons - cytology; p57; Repressor Proteins - genetics; Repressor Proteins - metabolism; Stem cells
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2011.486

Appropriate number of neurons and glial cells is generated from neural stem cells (NSCs) by the regulation of cell cycle exit and subsequent differentiation. Although the regulatory mechanism remains obscure, Id ( i nhibitor of d ifferentiation) proteins are known to contribute critically to NSC proliferation by controlling cell cycle. Here, we report that a transcriptional factor, RP58, negatively regulates all four Id genes ( Id1–Id4 ) in developing cerebral cortex. Consistently, Rp58 knockout (KO) mice demonstrated enhanced astrogenesis accompanied with an excess of NSCs. These phenotypes were mimicked by the overexpression of all Id genes in wild‐type cortical progenitors. Furthermore, Rp58 KO phenotypes were rescued by the knockdown of all Id genes in mutant cortical progenitors but not by the knockdown of each single Id gene. Finally, we determined p57 as an effector gene of RP58‐ Id ‐mediated cell fate control. These findings establish RP58 as a novel key regulator that controls the self‐renewal and differentiation of NSCs and restriction of astrogenesis by repressing all Id genes during corticogenesis. Neuronal stem cell differentiation during cortical development requires to exit cell cycle and p57 kinase regulation. Here, the transcription factor RP58 is shown to control neuronal differentiation and migration during embryogenesis by repressing all four Id genes, which in turn downregulates p57, thereby restricting astrogenesis.