The Secretory Pathway Calcium ATPase 1 (SPCA1) controls neural tube closure by regulating cytoskeletal dynamics

Abstract

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.

Global analysis of cell behavior and protein localization dynamics reveals region-specific functions for Shroom3 and N-cadherin during neural tube closure

“…Second, we show that changes in apical area in the anterior neural ectoderm are more strongly correlated with changes in medial actomyosin localization versus junctional actomyosin, indicating that contractility driving apical constriction is more likely to be generated at the medial cell surface. Our results on medial actin localization are largely consistent with smaller scale studies in both Xenopus and mice (Christodolou 2015, Suzuki 2017, Brown 2018) and moreover reflect mechanisms described in more detail in the context of Drosophila and C. elegans gastrulation (Martin et al, 2009; Roh-Johnson et al, 2012). Conversely, our data shows that both medial and junctional actin localization have similar correlations with apical area in the posterior neural ectoderm, suggesting actomyosin contractility may be more balanced across these medial and junctional domains in this region.…”

“…For example, analysis of apical constriction during gastrulation in both Drosophila and C. elegans has shown integration of discrete junctional and medio-apical (“medial”) populations of actomyosin (Coravos and Martin, 2016; Martin et al, 2009; Roh-Johnson et al, 2012). Recent studies in frog and chick embryos have also described similar pulsed medial actomyosin-based contractions occurring during neural tube closure (Brown and García-García, 2018; Christodoulou and Skourides, 2015; Suzuki et al, 2017), but how those contractions are controlled and how they contribute to cell shape change during neural tube closure are not known.…”

Cell non-autonomy amplifies disruption of neurulation by mosaic Vangl2 deletion

“…Neuroepithelial apical constriction has been documented in the mouse by ourselves and others 12,21,38,39 .…”

Crosstalk among Calcium ATPases: PMCA, SERCA and SPCA in Mental Diseases

“…Additionally, downregulation of SPCA1 disrupted the proper processes of neuronal growth and differentiation, leading to altered GA morphology (like its fragmentation), as well as slowed down protein transport in the Golgi compartments [ 194 ]. In neural tissue SPCA1 exhibited an important role in the control of cytoskeletal dynamics in mice neuroepithelial cells and perturbation of calcium homeostasis impaired apical constriction during neural tube closure [ 195 ]. Since the GA is an important platform for a number of signaling cascades, inactivation of SPCA1 can also induce the disturbances in mitochondrial structure and metabolism, increasing their sensitivity to stress conditions [ 196 ].…”