The PDZ domain protein Mcc is a novel effector of non-canonical Wnt signaling during convergence and extension in zebrafish

Abstract

During vertebrate gastrulation, a complex set of mass cellular rearrangements shapes the embryonic body plan and appropriately positions the organ primordia. In zebrafish and Xenopus, convergence and extension (CE) movements simultaneously narrow the body axis mediolaterally and elongate it from head to tail. This process is governed by polarized cell behaviors that are coordinated by components of the non-canonical, β-catenin-independent Wnt signaling pathway, including Wnt5b and the transmembrane planar cell polarity (PCP) protein Vangl2. However, the intracellular events downstream of Wnt/PCP signals are not fully understood. Here, we show that zebrafish mutated in colorectal cancer (mcc), which encodes an evolutionarily conserved PDZ domain-containing putative tumor suppressor, is required for Wnt5b/Vangl2 signaling during gastrulation. Knockdown of mcc results in CE phenotypes similar to loss of vangl2 and wnt5b, whereas overexpression of mcc robustly rescues the depletion of wnt5b, vangl2 and the Wnt5b tyrosine kinase receptor ror2. Biochemical experiments establish a direct physical interaction between Mcc and the Vangl2 cytoplasmic tail. Lastly, CE defects in mcc morphants are suppressed by downstream activation of RhoA and JNK. Taken together, our results identify Mcc as a novel intracellular effector of non-canonical Wnt5b/ Vangl2/Ror2 signaling during vertebrate gastrulation.

Systematic Analysis of Human Protein Phosphatase Interactions and Dynamics

“…See also Figure S6. signaling (Young et al, 2014). The occurrence of the PTN3/ VANGs/CRCM complex in our study postulates the activity of PTN3 at the interface of canonical Wnt/non-canonical PCP signaling pathways.…”

Glypican 4 and Mmp14 interact in regulating the migration of anterior endodermal cells by limiting extracellular matrix deposition

“…In contrast, Gpc4, but not Vangl2, is required for palate morphogenesis (Sisson et al, 2015) and pLLP migration (Venero Galanternik et al, 2016). Vangl2 and Gpc4 also play distinct roles in ECM assembly and cell-cell adhesion (Dohn et al, 2013), in MTOC polarization in gastrulating lateral mesodermal cells (Sepich et al, 2011), in membrane recruitment by Gpr125 (Li et al, 2013), and in recruitment of mutated in colorectal cancer (MCC) as a downstream effector (Young et al, 2014). Thus, Gpc4 and Vangl2 have distinct functions in a variety of processes during embryogenesis.…”

Title: Basal constriction during midbrain-hindbrain boundary morphogenesis is mediated by Wnt5b and Focal Adhesion Kinase

“…2A-D). To determine the functional significance of Wnt5b in MHBC basal constriction, we used the established wnt5b antisense-morpholino modified oligonucleotide (MO) to inhibit function (Lele et al, 2001;Robu et al, 2007;Young et al, 2014). One-cell stage embryos were co-injected with control MO or wnt5b splice-site targeting MO with mGFP and live confocal imaging employed to examine cell shape.…”