Alpha-Catulin, a New Player in a Rho Dependent Apical Constriction That Contributes to the Mouse Neural Tube Closure

Abstract

Coordination of actomyosin contraction and cell-cell junctions generates forces that can lead to tissue morphogenetic processes like the formation of neural tube (NT), however, its molecular mechanisms responsible for regulating and coupling this contractile network to cadherin adhesion remain to be fully elucidated. Here, using a gene trapping technology, we unveil the new player in this process, α-catulin, which shares sequence homology with vinculin and α-catenin. Ablation of α-catulin in mouse causes defective NT closure due to impairment of apical constriction, concomitant with apical actin and P-Mlc2 accumulation. Using a 3D culture model system, we showed that α-catulin localizes to the apical membrane and its removal alters the distribution of active RhoA and polarization. Actin cytoskeleton and P-Mlc2, downstream targets of RhoA, are not properly organized, with limited accumulation at the junctions, indicating a loss of junction stabilization. Our data suggest that α-catulin plays an important role during NT closure by acting as a scaffold for RhoA distribution, resulting in proper spatial activation of myosin to influence actin-myosin dynamics and tension at cell-cell adhesion.

Intrinsic Mechanical Cues and Their Impact on Stem Cells and Embryogenesis

“…In addition, actin and NMM II accumulate at the cell apex and at cell-cell junctions ( Sai and Ladher, 2008 ; Galea et al, 2017 ; Vijayraghavan and Davidson, 2017 ; Butler et al, 2019 ). Numerous studies in Xenopus and vertebrates state that AC and actomyosin contractility are required to regulate the bending and folding of the neural plate and formation of the medial hingepoint ( Zhou et al, 2009 ; Inoue et al, 2016 ; Nikolopoulou et al, 2017 ; Suzuki et al, 2017 ; Butler et al, 2019 ; Karpińska et al, 2020 ). The posterior neuropore (PNP) at the most caudal end of the neural tube is known to be under tension during closure.…”

“…Several studies have identified proteins such as vinculin and MARCKS that mediate the actomyosin contractility during neural tube closure ( Morriss-Kay and Tuckett, 1985 ; Stumpo et al, 1995 ; Xu et al, 1998 ). For instance, the protein Catulin A is a key player in Rho-mediated AC; Catulin A-/- mutants are embryonically lethal at E10.5 and neural tube fusion fails to occur at the hindbrain/cervical boundary ( Karpińska et al, 2020 ). Apical actin and nestin filaments did not form in the neuroepithelium of mutants, which was correlated with a lack of active RhoA signalling ( Karpińska et al, 2020 ).…”

“…For instance, the protein Catulin A is a key player in Rho-mediated AC; Catulin A-/- mutants are embryonically lethal at E10.5 and neural tube fusion fails to occur at the hindbrain/cervical boundary ( Karpińska et al, 2020 ). Apical actin and nestin filaments did not form in the neuroepithelium of mutants, which was correlated with a lack of active RhoA signalling ( Karpińska et al, 2020 ). A recent study identified the endocytic receptor Lrp2 as an integral mediator of membrane remodelling during AC.…”

Catulin reporter marks a heterogeneous population of invasive breast cancer cells with some demonstrating plasticity and participating in vascular mimicry

“…Catulin has also been proven to interact with dystrophin in the dystroglycan-dystrophin/utrophin complex, where dystroglycan mediates cell-ECM adhesion 20 – 23 . Our laboratory has also described that catulin plays an important role during mouse neural tube closure by acting as a scaffold for RhoA distribution, resulting in proper spatial activation of myosin to influence actin-myosin dynamics, and tension at cell–cell adhesion 24 . Additionally, it has been reported that catulin plays a critical role in cancer metastasis by activating the ILK-mediated Akt-NF-κB-αvβ3 signaling axis 25 .…”

Catulin Based Reporter System to Track and Characterize the Population of Invasive Cancer Cells in the Head and Neck Squamous Cell Carcinoma

“…The knockdown of catulin in hHNSCC cell lines dramatically decreases the migratory and invasive potential of those cells in vitro and the metastatic potential in xenotransplants in vivo, indicating an important role of this protein in the process of cancer metastasis [ 25 ]. Interestingly, the ablation of catulin during normal mouse development results in defects in neural tube closure due to aberrations in active RhoA distribution, actin-myosin dynamics, and tension at cell–cell adhesion, indicating the crucial role of this protein in cellular processes [ 26 ]. It has also been shown that catulin is highly expressed in malignant melanoma cells and is a key factor in tumor development, invasion, and metastasis due to the downregulation of E-cadherin and the upregulation of mesenchymal markers such as N-cadherin, Snail/Slug, and the matrix metalloproteinases 2 and 9 [ 27 ], as well as contributing to chemoresistance by the activation of NF-κB and AP-1 and the phosphorylation of ERK [ 28 ].…”