Cereblon Control of Zebrafish Brain Size by Regulation of Neural Stem Cell Proliferation
Cereblon Control of Zebrafish Brain Size by Regulation of Neural Stem Cell Proliferation
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DOI：
10.1016/j.isci.2019.04.007
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发表时间：
2019-05-31
期刊：
影响因子：
5.8
通讯作者：
Handa, Hiroshi
中科院分区：
文献类型：
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作者：
Ando, Hideki;Sato, Tomomi;Handa, Hiroshi
沙利度胺是一种致畸剂，通过与cereblon（CRBN）（CRL4 E3泛素连接酶复合物的底物受体亚基）相互作用，导致发育中婴儿的多种畸形。CRBN最初被报道为与常染色体隐性遗传的非综合征型轻度精神发育迟滞相关的基因。然而，CRBN在大脑发育过程中的功能在很大程度上仍然未知。在这里，我们证明了CRBN通过促进神经干细胞（NSCs）的增殖来促进大脑发育。在斑马鱼胚胎中敲除CRBN会损害大脑发育，导致大脑变小，用沙利度胺治疗也是如此。相比之下，CRBN的过度表达导致大脑扩大，导致NSC区域的扩大和早期脑区细胞增殖的增加，以及脑区域特异性基因和神经和胶质标记基因的表达扩大。这些结果表明，CRBN通过调节发育过程中NSC的增殖来确定脑大小。
Thalidomide is a teratogen that causes multiple malformations in the developing baby through its interaction with cereblon (CRBN), a substrate receptor subunit of the CRL4 E3 ubiquitin ligase complex. CRBN was originally reported as a gene associated with autosomal recessive non-syndromic mild mental retardation. However, the function of CRBN during brain development remains largely unknown. Here we demonstrate that CRBN promotes brain development by facilitating the proliferation of neural stem cells (NSCs). Knockdown of CRBN in zebrafish embryos impaired brain development and led to small brains, as did treatment with thalidomide. By contrast, overexpression of CRBN resulted in enlarged brains, leading to the expansion of NSC regions and increased cell proliferation in the early brain field and an expanded expression of brain region-specific genes and neural and glial marker genes. These results demonstrate that CRBN functions in the determination of brain size by regulating the proliferation of NSCs during development.