TGF-β signaling-mediated morphogenesis: modulation of cell adhesion via cadherin endocytosis

Abstract

The molecular mechanisms governing the cell behaviors underlying morphogenesis remain a major focus of research in both developmental biology and cancer biology. TGF-␤ ligands control cell fate specification via Smad-mediated signaling. However, their ability to guide cellular morphogenesis in a variety of biological contexts is poorly understood. We report on the discovery of a novel TGF-␤ signaling-mediated cellular morphogenesis occurring during vertebrate gastrulation. Activin/nodal members of the TGF-␤ superfamily induce the expression of two genes regulating cell adhesion during gastrulation: Fibronectin Leucine-rich Repeat Transmembrane 3 (FLRT3), a type I transmembrane protein containing extracellular leucine-rich repeats, and the small GTPase Rnd1. FLRT3 and Rnd1 interact physically and modulate cell adhesion during embryogenesis by controlling cell surface levels of cadherin through a dynamin-dependent endocytosis pathway. Our model suggests that cell adhesion can be dynamically regulated by sequestering cadherin through internalization, and subsequent redeploying internalized cadherin to the cell surface as needed. As numerous studies have linked aberrant expression of small GTPases, adhesion molecules such as cadherins, and TGF-␤ signaling to oncogenesis and metastasis, it is tempting to speculate that this FLRT3/Rnd1/cadherin pathway might also control cell behavior and morphogenesis in adult tissue homeostasis.[Keywords: GTPase; FLRT3; Rnd1; gastrulation; activin; Xenopus] Supplemental material is available at http://www.genesdev.org. During gastrulation, the three germ layers (ectoderm, mesoderm, and endoderm) establish new contacts, permitting new inductive interactions to specify the development of organ primordia. Some of the major movements that constitute gastrulation are convergence and extension, involution, and epiboly. The dynamic nature of cell-cell contacts in tissues undergoing these movements has been visualized using time-lapse video microscopy. Cells involved in convergence and extension movements are shown to continuously break and remake local adhesive contacts, via polarized membranous processes (e.g., lamellipodia), as they "slide" past one another during mediolateral intercalation (Davidson et al. 2002;Shook et al. 2004).Distinct adhesive properties conferred by adhesion molecules constitute a key feature of cells that undergo gastrulation movements. Type I cadherins are required for proper morphogenesis in sea urchin (Miller and McClay 1997), zebrafish (Montero et al. 2005;Shimizu et al. 2005), and mouse embryos (Riethmacher et al. 1995). Inactivation of C-cadherin, the primary mediator of adhesion in the Xenopus blastula, leads to both involution and convergent extension defects during gastrulation (Heasman et al. 1994). By changing the functional activity of C-cadherin at the cell surface, the morphogenetic elongation of "animal cap" ectodermal explants (mimicking the convergence and extension movements of the embryonic mesoderm) is altered (Brieher and Gumbiner 1994).The Wn...

Anchoring Junctions As Drug Targets: Role in Contraceptive Development

“…Numerous in vitro studies have also demonstrated that cytokines can cause integral membrane proteins such as E-cadherin and integrin to be internalized into endocytic vesicles, resulting in compromised cell adhesion. For instance, TGF-␤-mediated morphogenesis, which occurs during vertebrate gastrulation, resulted in cadherin internalization (Ogata et al, 2007). In addition, a similar endocytic trafficking mechanism was recently shown to exist in TGF-␤2-treated Sertoli cells having functional cell junctions (Yan et al, 2008), illustrating that this cytokine facilitates the disassembly of Sertoli cell adherens junctions to enable germ cells to traverse the blood-testis barrier.…”

“…Cadherins are target proteins of tumor necrosis factor-␣ (TNF-␣), transforming growth factor-␤ (TGF-␤), and interleukin-1␤ (IL-1␤) in multiple epithelia and endothelia, and this includes Sertoli cells in the testis (Karmakar and Das, 2004;Angelini et al, 2006;Li et al, 2006;Ogata et al, 2007). These cytokines were shown to reduce cadherin steady-state mRNA and/or protein levels, leading to adherens junction disassembly.…”

Sfrp5 coordinates foregut specification and morphogenesis by antagonizing both canonical and noncanonical Wnt11 signaling

“…This is similar to gastrulation where inhibition of Rac, Rho, or PKC activity is sufficient to inhibit CE movements. Wnt11 signaling has also been implicated in modulating E-cadherin-mediated cell cohesion, by regulating the dynamics of Rab5-mediated cadherin endocytosis and recycling to the membrane (Ulrich et al 2005;Witzel et al 2006;Ogata et al 2007). Sfrp5 might locally repress this activity and slow down cadherin cycling in the surface cells, leading to enhanced cell cohesion and allowing the formation of adherens junctions.…”

Genetic ablation of FLRT3 reveals a novel morphogenetic function for the anterior visceral endoderm in suppressing mesoderm differentiation

“…FLRTs also promote homotypic cell sorting, independent of FGFR signaling, in mammalian cells or Xenopus embryos, possibly by acting as homophilic cell adhesion molecules (Karaulanov et al 2006). Conversely, FLRT3 was shown to promote deadhesion of migrating animal cap cells during Xenopus gastrulation through the internalization of C-cadherin (Ogata et al 2007). Genetic deletion of FLRT3 in the mouse resulted in ventral closure and headfold fusion defects suggesting that FLRT3 may be required for tissue fusion (Maretto et al 2008).…”