Tre1 GPCR Signaling Orients Stem Cell Divisions in the Drosophila Central Nervous System

Abstract

During development, directional cell division is a major mechanism for establishing the orientation of tissue growth. Drosophila neuroblasts undergo asymmetric divisions perpendicular to the overlying epithelium to produce descendant neurons on the opposite side, thereby orienting initial neural tissue growth. However, the mechanism remains elusive. We provide genetic evidence that extrinsic GPCR signaling determines the orientation of cortical polarity underlying asymmetric divisions of neuroblasts relative to the epithelium. The GPCR Tre1 activates the G protein oα subunit in neuroblasts by interacting with the epithelium to recruit Pins, which regulates spindle orientation. Because Pins associates with the Par-complex via Inscuteable, Tre1 consequently recruits the polarity complex to orthogonally orient the polarity axis to the epithelium. Given the universal role of the Par complex in cellular polarization, we propose that the GPCR-Pins system is a comprehensive mechanism controlling tissue polarity by orienting polarized stem cells and their divisions.

Drosophila neuroblasts: a model for stem cell biology

“…They retain apical localization of the Par complex Fig. 3, Par3/Bazooka, Par-6 and atypical PKC; aPKC) and undergo multiple rounds of asymmetric cell divisions along the apical-basal axis of the overlying epithelium (Yoshiura et al, 2011). Subsequent embryonic divisions (Rebollo et al, 2009) and divisions of larval NBs (Rebollo et al, 2007;Rusan and Peifer, 2007) are, by contrast, aligned relative to the axis of the previous division.…”

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

“…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).…”

“…The Tre1 gene encodes an orphan rhodopsin family G-protein-coupled receptor (GPCR) required for transepithelial migration of germ cells (Kunwar et al 2003) and asymmetrical neuroblast division (Yoshiura et al 2012). Tre1 was originally misidentified as a trehalose receptor (Ishimoto et al 2000;Dahanukar et al 2001;Ueno et al 2001) due to its structural similarities to Drosophila gustatory receptors.…”

Genetic mechanisms regulating proliferation and cell specification in the Drosophila embryonic CNS

“…Tre1 activates Go protein in a classical GPCR-dependent manner [147]. Tre1 activation leads to Go physically binding to Pins and to recruit Pins-Insc, and consequentially Par-C to the basal pole, thereby organizing polarization and spindle orientation of NBs on tissue polarity [148].…”