Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA.
Department of Molecular Biology and Genetics, Cornell University, Ithaca, NY 14853, USA
Development. 2018 Oct 5;145(19):dev170019. doi: 10.1242/dev.170019.
Neural tube closure relies on the apical constriction of neuroepithelial cells. Research in frog and fly embryos has found links between the levels of intracellular calcium, actomyosin dynamics and apical constriction. However, genetic evidence for a role of calcium in apical constriction during mammalian neurulation is still lacking. Secretory pathway calcium ATPase (SPCA1) regulates calcium homeostasis by pumping cytosolic calcium into the Golgi apparatus. Loss of function in causes cranial exencephaly and spinal cord defects in mice, phenotypes previously ascribed to apoptosis. However, our characterization of a novel allele of revealed that neurulation defects in mutants are not due to cell death, but rather to a failure of neuroepithelial cells to apically constrict. We show that SPCA1 influences cell contractility by regulating myosin II localization. Furthermore, we found that loss of disrupts actin dynamics and the localization of the actin remodeling protein cofilin 1. Taken together, our results provide evidence that SPCA1 promotes neurulation by regulating the cytoskeletal dynamics that promote apical constriction and identify cofilin 1 as a downstream effector of SPCA1 function.
神经管闭合依赖于神经上皮细胞的顶端收缩。在青蛙和苍蝇胚胎中的研究发现细胞内钙水平、肌动球蛋白动力学和顶端收缩之间存在联系。然而，在哺乳动物神经胚发生过程中钙在顶端收缩中的作用的遗传证据仍然缺乏。分泌途径钙 ATP 酶 (SPCA1) 通过将细胞质钙泵入高尔基体来调节钙稳态。在小鼠中，功能丧失导致颅面裂和脊髓缺陷，这些表型以前归因于细胞凋亡。然而，我们对 SPCA1 的一种新等位基因的特征描述表明，SPCA1 突变体中的神经胚发生缺陷不是由于细胞死亡，而是由于神经上皮细胞不能进行顶端收缩。我们表明 SPCA1 通过调节肌球蛋白 II 的定位来影响细胞收缩性。此外，我们发现缺失 SPCA1 会破坏肌动蛋白动力学和肌动蛋白重塑蛋白 cofilin 1 的定位。总之，我们的结果提供了证据表明 SPCA1 通过调节促进顶端收缩的细胞骨架动力学来促进神经胚发生，并确定 cofilin 1 是 SPCA1 功能的下游效应物。
