Tre1 GPCR initiates germ cell transepithelial migration by regulating Drosophila melanogaster E-cadherin

Abstract

Despite significant progress in identifying the guidance pathways that control cell migration, how a cell starts to move within an intact organism, acquires motility, and loses contact with its neighbors is poorly understood. We show that activation of the G protein–coupled receptor (GPCR) trapped in endoderm 1 (Tre1) directs the redistribution of the G protein Gβ as well as adherens junction proteins and Rho guanosine triphosphatase from the cell periphery to the lagging tail of germ cells at the onset of Drosophila melanogaster germ cell migration. Subsequently, Tre1 activity triggers germ cell dispersal and orients them toward the midgut for directed transepithelial migration. A transition toward invasive migration is also a prerequisite for metastasis formation, which often correlates with down-regulation of adhesion proteins. We show that uniform down-regulation of E-cadherin causes germ cell dispersal but is not sufficient for transepithelial migration in the absence of Tre1. Our findings therefore suggest a new mechanism for GPCR function that links cell polarity, modulation of cell adhesion, and invasion.

A Novel Gene Controlling the Timing of Courtship Initiation in Drosophila melanogaster

“…Mutation of this gene leads not only to rapid courtship initiation, but, unlike males in which the Tre1 cells are feminized, Tre1 mutant males also frequently fail to copulate and are at a reproductive disadvantage relative to wild-type males. Future studies will focus on characterization of the downstream components of the Tre1 signal transduction pathway, which likely include the trimeric G-protein subunits Gg1 and Gb13f (Kunwar et al 2008) as well as identification of the Tre1 ligand.…”

“…In migrating germ cells, the role of Tre1 appears to be to change the polarity of the cells such that they are oriented toward their ultimate target, and to facilitate the loss of cell-cell adhesion between germ cells, thereby priming the cells to be receptive to further guidance signals (Kunwar et al 2008).…”

“…Tre1 is required for initiation of transepithelial migration in Drosophila germ cells (Kunwar et al 2003(Kunwar et al , 2008, neuroblast polarity during asymmetric stem cell division in the developing central nervous system (Yoshiura et al 2012). The ligand for Tre1 is not known, but based on sequence similarity, belongs to a family of proteins related to the GPCR CXCR4, which, together with its ligand SDF1, is required for germ cell migration in vertebrates (Kunwar et al 2003).…”

“…Both the cell migration and cell polarity roles for Tre1 reflect activation of heterotrimeric G-protein signaling that ultimately leads to polarization of the cytoskeleton (and, in the case of germ cell migration, polarized distribution of E-cadherin) (Kunwar et al 2008;Yoshiura et al 2012). In migrating germ cells, the role of Tre1 appears to be to change the polarity of the cells such that they are oriented toward their ultimate target, and to facilitate the loss of cell-cell adhesion between germ cells, thereby priming the cells to be receptive to further guidance signals (Kunwar et al 2008).…”

Primordial germ cell migration and the Wnt signaling pathway

“…Shortly thereafter, the PGCs begin to express Tre1, which polarizes the cells and initiates their individual dispersal through the epithelial layer midgut endoderm ( Fig. 1; Kunwar et al, 2008). Once outside the midgut, Drosophila PGCs migrate dorsally then anteriorly along the midgut, incorporate into the posterior mesoderm, and bifurcate laterally to join somatic gonadal precursor cells (SGPCs) and form the gonads (Sonnenblick, 1941;Warrior, 1994).…”