Latrophilin-1 drives neuron morphogenesis and shapes chemo- and mechanosensation-dependent behavior in C. elegans via a trans function.

Latrophilins are highly conserved Adhesion GPCRs playing essential roles in the mammalian nervous system and are associated with severe neurological disorders. Recently, it has been shown that murine Latrophilins mediate classical G-protein signals to drive synaptogenesis. However, there is evidence that Latrophilins in the nematode Caenorhabditis elegans can also function independently of their seven-transmembrane domain and C terminus (trans function). Here, we show that Latrophilin-1 acts in trans to mediate morphogenesis of sensory structures in the C. elegans nervous system. This trans function is physiologically relevant in copulation behavior. Detailed expression and RNA-Seq analyses revealed specific LAT-1-positive neurons and first insights into the genetic network that is modulated by the receptor function. We conclude that 7TM-independent functions of Latrophilins are essential for neuronal physiology, possibly complementing canonical functions via G protein-mediated signaling.

The N terminus-only (trans) function of the Adhesion GPCR Latrophilin-1 controls multiple processes in reproduction of C. elegans.

Adhesion G protein-coupled receptors (aGPCR) are unique molecules. They are able to transmit classical signals via G-protein activation as well as mediate functions solely through their extracellular N termini, completely independently of the seven transmembrane helices domain (7TM) and the C terminus. This dual mode of action is highly unusual for GPCRs and allows for a plethora of possible cellular consequences. However, the physiological implications and molecular details of this N terminus-mediated signaling are poorly understood. Here, we show that several distinct 7TM-independent/trans functions of the aGPCR Latrophilin homolog LAT-1 in the nematode Caenorhabditis elegans together regulate reproduction: sperm guidance, ovulation, and germ cell apoptosis. In these contexts, the receptor elicits its functions in a non-cell autonomous manner. The functions might be realized through alternative splicing of the receptor specifically generating N terminus-only variants. Thus, our findings shed light on the versatility of 7TM-independent/N terminus-only/trans functions of aGPCR and discuss possible molecular details.

The adhesion GPCR and PCP component flamingo (FMI-1) alters body size and regulates the composition of the extracellular matrix.

The extracellular matrix (ECM) is a network of macromolecules that presents a vital scaffold for cells and enables multiple ways of cellular communication. Thus, it is essential for many physiological processes such as development, tissue morphogenesis, homeostasis, the shape and partially the size of the body and its organs. To ensure these, the composition of the ECM is tissue-specific and highly dynamic. ECM homeostasis is therefore tightly controlled by several mechanisms. Here, we show that FMI-1, the homolog of the Adhesion GPCR Flamingo/CELSR/ADGRC in the nematode Caenorhabditis elegans, modulates the composition of the ECM by controlling the production both of ECM molecules such as collagens and also of ECM modifying enzymes. Thereby, FMI-1 affects the morphology and functionality of the nematode´s cuticle, which is mainly composed of ECM, and also modulates the body size. Mechanistic analyses highlight the fact that FMI-1 exerts its function from neurons non-cell autonomously (trans) solely via its extracellular N terminus. Our data support a model, by which the activity of the receptor, which has a well-described role in the planar cell polarity (PCP) pathway, involves the PCP molecule VANG-1, but seems to be independent of the DBL-1/BMP pathway.