Protein phosphatase 1 regulatory subunit 35 is required for ciliogenesis, notochord morphogenesis, and cell-cycle progression during murine development.
Protein phosphatase 1 regulatory subunit 35 is required for ciliogenesis, notochord morphogenesis, and cell-cycle progression during murine development.
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蛋白磷酸酶 1 调节亚基 35 是小鼠发育过程中纤毛发生、脊索形态发生和细胞周期进展所必需的。
DOI：
10.1016/j.ydbio.2020.06.011
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发表时间：
2020
影响因子：
2.7
通讯作者：
Mager,Jesse
中科院分区：
文献类型：
--
作者：
Archambault,Danielle;Cheong,Agnes;Iverson,Elizabeth;Tremblay,KimberlyD;Mager,Jesse
蛋白磷酸酶通过翻译后修饰调节多种蛋白质，并且是真核生物中大量细胞内事件所必需的。虽然蛋白磷酸酶复合物的一些核心成分被很好地表征，但这些大复合物的许多亚基仍未被研究。在这里，我们的特点是蛋白磷酸酶1调节亚基35（Ppp 1 r35）基因的功能丧失等位基因。缺失Ppp 1 r35的纯合子小鼠胚胎从胚胎第7.5天开始发育延迟，并在后期出现明显的形态缺陷。突变体不能启动转向，也不能超过正常E8.5胚胎的大小或分期。与最近将PPP 1 R35与小头畸形蛋白Rotatin联系起来的体外研究以及与中心体形成的作用相一致，我们发现PPP 1 R35突变胚胎缺乏初级纤毛。Ppp 1 r35突变体的组织学和分子分析显示，脊索发育是不规则和不连续的，与初级纤毛中的作用一致，神经管的底板未指定。与其他中心粒功能缺陷的突变体胚胎相似，Ppp 1 r35突变体显示神经管中普遍存在的细胞死亡增加和前中期增殖细胞数量增加。我们推测，Ppp 1 r35功能的损失废除中心粒稳态，导致未能产生功能性初级纤毛，细胞死亡和细胞周期延迟/停滞，导致发育失败。综上所述，这些结果突出了Ppp 1 r35在早期哺乳动物发育过程中的重要功能，并暗示该基因是人类小头畸形的候选基因。
Protein phosphatases regulate a wide array of proteins through post-translational modification and are required for a plethora of intracellular events in eukaryotes. While some core components of the protein phosphatase complexes are well characterized, many subunits of these large complexes remain unstudied. Here we characterize a loss-of-function allele of the protein phosphatase 1 regulatory subunit 35 (Ppp1r35) gene. Homozygous mouse embryos lackingPpp1r35are developmental delayed beginning at embryonic day (E) 7.5 and have obvious morphological defects at later stages. Mutants fail to initiate turning and do not progress beyond the size or staging of normal E8.5 embryos. Consistent with recentin vitrostudies linking PPP1R35 with the microcephaly protein Rotatin and with a role in centrosome formation, we show thatPpp1r35mutant embryos lack primary cilia. Histological and molecular analysis ofPpp1r35mutants revealed that notochord development is irregular and discontinuous and consistent with a role in primary cilia, that the floor plate of the neural tube is not specified. Similar to other mutant embryos with defects in centriole function,Ppp1r35mutants displayed increased cell death that is prevalent in the neural tube and an increased number of proliferative cells in prometaphase. We hypothesize that loss ofPpp1r35function abrogates centriole homeostasis, resulting in a failure to produce functional primary cilia, cell death and cell cycle delay/stalling that leads to developmental failure. Taken together, these results highlight the essential function ofPpp1r35during early mammalian development and implicate this gene as a candidate for human microcephaly.