Latrophilin Signaling Links Anterior-Posterior Tissue Polarity and Oriented Cell Divisions in the C. elegans Embryo

Abstract

SUMMARY Understanding the mechanisms that coordinate the orientation of cell division planes during embryogenesis and morphogenesis is a fundamental problem in developmental biology. Here we show that the orphan receptor lat-1, a homolog of vertebrate latrophilins, plays an essential role in the establishment of tissue polarity in the C. elegans embryo. We provide evidence that lat-1 is required for the alignment of cell division planes to the anterior-posterior axis and acts in parallel to known polarity and morphogenesis signals. lat-1 is a member of the Adhesion-GPCR protein family and is structurally related to flamingo/CELSR, an essential component of the planar cell polarity pathway. We dissect the molecular requirements of lat-1 signaling and implicate lat-1 in an anterior-posterior tissue polarity pathway in the pre-morphogenesis stage of C. elegans development.

Characterization and functional study of a cluster of four highly conserved orphan adhesion‐GPCR in mouse

“…The nematode system allows rapid and highly scalable testing of molecular requirements for aGPCR function in vivo by means of transgenic introduction of receptor variants in an aGPCR null background. We have used this strategy to systematically uncover the requirement of conserved protein domains in the N terminus of the latrophilin-type aGPCR LAT-1 (Vakonakis et al, 2008;Langenhan et al, 2009). Using this approach, we have recently shown that cleavage at the GPS motif is not necessary for activity of LAT-1 in development and fertility, that the ''splitpersonality'' hypothesis, the ambiguous pairing of cleaved N-and C-terminal subunits of different aGPCR (Silva et al, 2009), is not required for LAT-1 function in the worm, and that two different signal activities are relayed through the LAT-1 receptor (Pr€ omel et al, 2012).…”

“…In addition to dissecting molecular dependencies of aGPCR signals, the worm also permits analysis of genetic interactions for the two invertebrate aGPCR groups, latrophilins and Flamingo/CELSR, under physiological conditions. Using the nematode toolkit, we implicated latrophilins in anterior-posterior tissue polarity in the nematode, a previously unknown property of latrophilins (Langenhan et al, 2009).…”

The adhesion GPCR latrophilin – a novel signaling cascade in oriented cell division and anterior-posterior polarity

“…Nematodes homozygous for the null mutant allele lat-1(ok1465) (referred to lat-1 hereafter) show severe defects in embryonic and larval development leading to only a small number of individuals passing developmental stages and reaching adulthood. 6 Previous studies revealed that the spindle of ABal, one of the AB4 blastomeres in the 8-cell stage embryo, is turned almost perpendicular to the anterior-posterior axis in which this cell normally divides, suggesting that anterior-posterior polarity is disturbed (Fig. 1).…”

“…6,14 However, its role in oriented cell division and anterior-posterior polarity is the most thoroughly studied one. Nematodes homozygous for the null mutant allele lat-1(ok1465) (referred to lat-1 hereafter) show severe defects in embryonic and larval development leading to only a small number of individuals passing developmental stages and reaching adulthood.…”

“…The latrophilin/ADGRL homolog LAT-1 has been recently identified as a novel candidate molecule being involved in this process as it is required for the coordination of spindle orientation at this stage of embryonic development. 6 Being originally described as receptor for the black widow spider's (Latrodectus mactans) toxin 7,8 LAT-1 belongs to the adhesion G protein-coupled receptors (adhesion GPCRs). This class of receptors is considered to play dual roles in cell-cell or cell-matrix adhesion and transmembrane signaling, 9-11 making them interesting molecules in the establishment and maintenance of polarity.…”