UTX deficiency in neural stem/progenitor cells results in impaired neural development, fetal ventriculomegaly, and postnatal death
UTX deficiency in neural stem/progenitor cells results in impaired neural development, fetal ventriculomegaly, and postnatal death
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DOI：
10.1096/fj.202201002rr
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发表时间：
2022-11
期刊：
影响因子：
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通讯作者：
M. Koizumi;Hikaru Eto;Mai Saeki;Masahide Seki;T. Fukushima;S. Mukai;H. Ide;Y. Sera;Masayuki Iwasaki;Yutaka Suzuki;A. Tohei;Y. Kishi;H. Honda
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作者：
M. Koizumi;Hikaru Eto;Mai Saeki;Masahide Seki;T. Fukushima;S. Mukai;H. Ide;Y. Sera;Masayuki Iwasaki;Yutaka Suzuki;A. Tohei;Y. Kishi;H. Honda
最近的研究表明，表观遗传修饰深深地参与了神经发生;然而，确切的机制仍然在很大程度上未知。为了确定UTX（也称为KDM 6A）（一种组蛋白H3 K27的脱甲基酶）在神经发育中的作用，我们在神经干/祖细胞（NSPCs）中产生了UTX缺陷小鼠。由于Utx是X染色体特异性基因，因此基因型具有性别依赖性;雌性小鼠丢失两个Utx等位基因（UtxΔ/Δ），雄性小鼠丢失一个Utx等位基因，但保留一个Uty等位基因，即Y染色体上的Utx对应基因（UtxΔ/Uty）。我们发现，UtxΔ/Δ小鼠表现出胎儿脑室扩大，出生后不久死亡。免疫荧光染色和EdU标记显示NSPCs显著增加，中间祖细胞和分化的神经细胞显著减少。分子生物学分析显示，UtxΔ/Δ NSPCs中与DNA复制相关的通路下调，转录起始位点周围的H3 K27 me 3水平升高。这些结果表明，UTX在整体上调节NSPCs中适当神经发育所需的基因的表达，并且UTX缺乏导致细胞周期退出受损、分化降低和新生儿死亡。有趣的是，尽管UtxΔ/Uty小鼠在出生后存活，但大多数死于脑积水，这是Kabuki综合征的一种临床特征，是一种涉及UTX突变的先天性异常。我们的研究结果为组蛋白修饰剂在神经发育中的作用提供了新的见解，并表明UtxΔ/Uty小鼠是歌舞伎综合征的潜在疾病模型。
Recent studies have demonstrated that epigenetic modifications are deeply involved in neurogenesis; however, the precise mechanisms remain largely unknown. To determine the role of UTX (also known as KDM6A), a demethylase of histone H3K27, in neural development, we generated Utx‐deficient mice in neural stem/progenitor cells (NSPCs). Since Utx is an X chromosome‐specific gene, the genotypes are sex‐dependent; female mice lose both Utx alleles (UtxΔ/Δ), and male mice lose one Utx allele yet retain one Uty allele, the counterpart of Utx on the Y chromosome (UtxΔ/Uty). We found that UtxΔ/Δ mice exhibited fetal ventriculomegaly and died soon after birth. Immunofluorescence staining and EdU labeling revealed a significant increase in NSPCs and a significant decrease in intermediate‐progenitor and differentiated neural cells. Molecular analyses revealed the downregulation of pathways related to DNA replication and increased H3K27me3 levels around the transcription start sites in UtxΔ/Δ NSPCs. These results indicate that UTX globally regulates the expression of genes required for proper neural development in NSPCs, and UTX deficiency leads to impaired cell cycle exit, reduced differentiation, and neonatal death. Interestingly, although UtxΔ/Uty mice survived the postnatal period, most died of hydrocephalus, a clinical feature of Kabuki syndrome, a congenital anomaly involving UTX mutations. Our findings provide novel insights into the role of histone modifiers in neural development and suggest that UtxΔ/Uty mice are a potential disease model for Kabuki syndrome.