The non-canonical Wnt-PCP pathway shapes the caudal neural plate

Abstract

The last stage of neural tube (NT) formation involves closure of the caudal neural plate (NP), an embryonic structure formed by neuromesodermal progenitors and newly differentiated cells that becomes incorporated into the NT. Here, we show in mouse that, as cell specification progresses, neuromesodermal progenitors and their progeny undergo significant changes in shape prior to their incorporation into the NT. The caudo-rostral progression towards differentiation is coupled to a gradual reliance on a unique combination of complex mechanisms that drive tissue folding, involving pulses of apical actomyosin contraction and planar polarised cell rearrangements, all of which are regulated by the Wnt-PCP pathway. Indeed, when this pathway is disrupted, either chemically or genetically, the polarisation and morphology of cells within the entire caudal NP is disturbed, producing delays in NT closure. The most severe disruptions of this pathway prevent caudal NT closure and result in spina bifida. In addition, a decrease in gene dosage also appears to promote more rapid progression towards a neural fate, but not the specification of more neural cells.

Apical restriction of the planar cell polarity component VANGL in pancreatic ducts is required to maintain epithelial integrity

“…Actomyosin contraction, mediated by activation of Rho kinase, is well-recognised as an important downstream effector of the PCP 11, 27, 28 and VANGL, in particular, has been involved in remodeling of actin microfilaments 29–33 . Moreover, actomyosin contractility is associated with apoptosis in different contexts 34 .…”

The interaction of maternal diabetes with mutations that affect folate metabolism and how they affect the development of neural tube defects in mice

“…When the morphology of the PNP was analyzed histologically, it was altered in embryos exposed to homocysteine or glucose, and more severely in those exposed to glucose and homocysteine, resembling the effect in embryos in which apical actin microfilament assembly is impaired or the binding of accessory proteins was disrupted. This morphological change is the direct consequence of losing the tension created by apical actin microfilament contractions that are necessary for cells to assume a wedge‐like shape, which is essential for correct folding of the neural plate …”

“…Diabetes‐induced morphogenetic defects have been associated with changes in gene expression, and several have been linked to embryopathies (like Pax3 ) or genes involved in Wnt signaling . Alterations to the Wnt‐PCP pathway disrupt the distribution of apical actin microfilaments in the caudal and cranial neural plate, and this disrupts the polarization and morphology of the cells in this region, delaying NT closure and possibly driving NTDs . Activation of Wnt‐PCP signaling induces the formation of a Daam1‐Dishevelled‐RhoA complex that activates its downstream effector ROCK, provoking actin cytoskeletal remodeling .…”

“…This morphological change is the direct consequence of losing the tension created by apical actin microfilament contractions that are necessary for cells to assume a wedge-like shape, which is essential for correct folding of the neural plate. [67][68][69] Diabetes-induced morphogenetic defects have been associated with changes in gene expression, and several have been linked to embryopathies (like Pax3) or genes involved in Wnt signaling. 7,8,10,51,56,57 Alterations to the Wnt-PCP pathway disrupt the distribution of apical actin microfilaments in the caudal and cranial neural plate, and this disrupts the polarization and morphology of the cells in this region, delaying NT closure and possibly driving NTDs.…”

“…7,8,10,51,56,57 Alterations to the Wnt-PCP pathway disrupt the distribution of apical actin microfilaments in the caudal and cranial neural plate, and this disrupts the polarization and morphology of the cells in this region, delaying NT closure and possibly driving NTDs. 67,70,71 Activation of Wnt-PCP signaling induces the formation of a Daam1-Dishevelled-RhoA complex that activates its downstream effector ROCK, provoking actin cytoskeletal remodeling. 72,73 Alternatively, cofilin phosphorylation, a protein that lies downstream of Rho GTPases and that facilitates dynamic reorganization of the actin cytoskeleton, requires the activation of LIMK1 by FA.…”