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The adhesion GPCR BAI3 is an orphan receptor that has a long N-terminus consisting of one cub domain, five Bal thrombospondin type 1 repeats, and one hormone binding domain.
BAI3 regulate Rac pathway
Muscle fibers are formed after fusion of muscle cells, but cell surface receptors that regulate this process are not known in vertebrates. Genetic screening of Drosophila reveals cytoskeletal regulators, including myoblast city (mbc, ortholog of Dock1) and Rac, which specifically control the myoblast fusion step. Dock1 and Rac1 mutated in mice were generated to address whether this pathway plays a universal role in myoblast fusion. Mutants die at birth and are characterized by a strong block of fusion in primary myoblasts in vivo and in vitro. Similarly, muscle-specific inactivation of Rac1 severely impairs myoblast fusion. Looking for regulators of myoblast fusion, Noumeira et al. identified the G-protein coupled receptor brain-specific angiogenesis inhibitor (BAI3) as a cell surface protein that interacts with engulfment and cell motility (ELMO). In cultured cells, loss of BAI3 or ELMO1/2 function severely impairs myoblast fusion without affecting differentiation and cannot be rescued by re-expressing BAI3 mutants lacking ELMO binding. The related BAI protein family member ember BAI1 is functionally different from BAI3 because it does not rescue myoblast fusion defects caused by loss of BAI3 function. Finally, embryonic muscle precursor expression that does not bind to ELMO's BAI3 mutant is sufficient to block myoblast fusion in vivo.
Collectively, the BAI3 plays an important role in extracellular fusion signaling to intracellular effectors, identifying it as an essential transmembrane protein for embryonic vertebrate myoblast fusion.
Fig. 1. BAI3 is expressed by myoblasts and is essential for myoblast fusion. (Laurin M et al. Genes & Development. 2014.).
Regulation of dendritic morphogenesis involves the integration of extracellular signals and intrinsic molecular programs to control the growth and branching of the actin cytoskeleton. The BAI receptors are new regulators of this process that can sense extracellular signals and Intracellular signal by interaction with effectors such as ELMO1. The BAI3 receptor was also found to localize to actin-rich cell processes, such as filopodia and lamelipodia in HEK-293H cells, as well as dendrites. V Lanoue et al. has shown that overexpression of the BAI3 receptor inhibits cell spreading through its cytoplasmic tail, partially through ELMO1, indicating that BAI3 signaling can indeed regulate dendritic morphogenesis through Rac regulation. BAI3’s interaction with ELMO1 constitutes a direct pathway linking extracellular cues and intracellular modification of the actin cytoskeleton during neuronal development.
BAI3 is a high-affinity receptor for C1q-like proteins
The C1q-like (C1q1) protein is a small secreted protein belonging to a large family of proteins containing a globular complementary 1Q (gC1q) domain that binds to form a homo-trimer or a hetero-trimer. The C1q1 and BAI3 proteins are expressed almost exclusively in the brain in adult animals and appear to be enriched in neurons. Strikingly, the addition of the recombinant gC1q domains of C1ql proteins to the medium of cultured hippocampal neurons caused significant decreases in synapse density without affecting other measured morphological parameters. Bolliger et al. revealed that the thrombospondin repeats of BAI3 were both necessary and sufficient to bind to C1ql3, and the BAI3 fragment binding to C1ql3 blocked the effect of C1ql3 on synapse density.