RP58/ZNF238 directly modulates proneurogenic gene levels and is required for neuronal differentiation and brain expansion

被引:62
作者
Xiang, C. [1 ]
Baubet, V. [1 ]
Pal, S. [1 ]
Holderbaum, L. [1 ]
Tatard, V. [1 ]
Jiang, P. [1 ]
Davuluri, R. V. [1 ]
Dahmane, N. [1 ]
机构
[1] Wistar Inst Anat & Biol, Philadelphia, PA 19104 USA
关键词
RP58; ZNF238; BTB/POZ; neurogenic progenitors; cerebral cortex; microcephaly; INTERMEDIATE PROGENITOR CELLS; CEREBRAL-CORTEX DEVELOPMENT; RADIAL GLIA; CORPUS-CALLOSUM; NERVOUS-SYSTEM; DEVELOPING NEOCORTEX; CRITICAL REGION; NEURAL STEM; NEUROGENESIS; EXPRESSION;
D O I
10.1038/cdd.2011.144
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Although neurogenic pathways have been described in the developing neocortex, less is known about mechanisms ensuring correct neuronal differentiation thus also preventing tumor growth. We have shown that RP58 (aka zfp238 or znf238) is highly expressed in differentiating neurons, that its expression is lost or diminished in brain tumors, and that its reintroduction blocks their proliferation. Mice with loss of RP58 die at birth with neocortical defects. Using a novel conditional RP58 allele here we show that its CNS-specific loss yields a novel postnatal phenotype: microencephaly, agenesis of the corpus callosum and cerebellar hypoplasia that resembles the chr1qter deletion microcephaly syndrome in human. RP58 mutant brains maintain precursor pools but have reduced neuronal and increased glial differentiation. Well-timed downregulation of pax6, ngn2 and neuroD1 depends on RP58 mediated transcriptional repression, ngn2 and neuroD1 being direct targets. Thus, RP58 may act to favor neuronal differentiation and brain growth by coherently repressing multiple proneurogenic genes in a timely manner. Cell Death and Differentiation (2012) 19, 692-702; doi:10.1038/cdd.2011.144; published online 18 November 2011
引用
收藏
页码:692 / 702
页数:11
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