Aoki Hitomi
Department of Tissue and Organ Development, Regeneration, and Advanced Medical Science, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, 501-1194, Japan.
Med Mol Morphol. 2018 Sep;51(3):129-138. doi: 10.1007/s00795-018-0187-x. Epub 2018 Mar 13.
Rest is a regulator of neuronal development and has been suggested to function in maintaining the pluripotent state of embryonic stem cells (ESCs); however, this remains controversial. Since Rest null mice show embryonic lethality, we herein generated conditional Rest knockout (CKO) models to investigate Rest functions in more detail. Our results revealed that Rest was not necessary for maintaining the pluripotency of ESCs and instead promoted primitive endoderm differentiation. In contrast to the repressive role of Rest in vitro, including ESCs, neural stem cells, and fibroblasts, on the expression of target neural genes, Rest CKO did not affect the in vivo development of brain tissue. However, the same Rest CKO mice showed an abnormal lens morphology after birth with augmented Notch signaling and down-regulated lens fiber regulator gene expression. The ablation of Rest during neural crest cell (NCC) development caused neonatal lethality due to swelling of the digestive tract with reductions in acetylcholinesterase activity in the myenteric plexus derived from NCCs. Furthermore, a reduced number of melanocyte precursors also derived from NCCs resulted in white spotted coat color phenotypes lacking mature melanocytes. Rest controls thousands of target genes and may have many unknown functions related to diseases.
REST是神经元发育的调节因子，有人认为它在维持胚胎干细胞（ESC）的多能状态中发挥作用；然而，这一点仍存在争议。由于Rest基因敲除小鼠表现出胚胎致死性，我们在此构建了条件性Rest基因敲除（CKO）模型，以更详细地研究Rest的功能。我们的结果显示，Rest对于维持ESC的多能性并非必需，相反，它促进了原始内胚层的分化。与Rest在体外（包括ESC、神经干细胞和成纤维细胞）对靶神经基因表达的抑制作用相反，Rest基因敲除并不影响脑组织的体内发育。然而，同样的Rest基因敲除小鼠出生后晶状体形态异常，Notch信号增强，晶状体纤维调节基因表达下调。在神经嵴细胞（NCC）发育过程中Rest的缺失导致新生儿死亡，原因是消化道肿胀，源自NCC的肌间神经丛中乙酰胆碱酯酶活性降低。此外，同样源自NCC的黑素细胞前体数量减少，导致缺乏成熟黑素细胞的白色斑点毛色表型。Rest控制着数千个靶基因，可能还有许多与疾病相关的未知功能。
