The Adhesion-GPCR BAI1 Regulates Synaptogenesis by Controlling the Recruitment of the Par3/Tiam1 Polarity Complex to Synaptic Sites

Abstract

Excitatory synapses are polarized structures that primarily reside on dendritic spines in the brain. The small GTPase Rac1 regulates the development and plasticity of synapses and spines by modulating actin dynamics. By restricting the Rac1-guanine nucleotide exchange factor Tiam1 to spines, the polarity protein Par3 promotes synapse development by spatially controlling Rac1 activation. However, the mechanism for recruiting Par3 to spines is unknown. Here, we identify brain-specific angiogenesis inhibitor 1 (BAI1) as a synaptic adhesion GPCR that is required for spinogenesis and synaptogenesis in mice and rats. We show that BAI1 interacts with Par3/Tiam1 and recruits these proteins to synaptic sites. BAI1 knockdown results in Par3/Tiam1 mislocalization and loss of activated Rac1 and filamentous actin from spines. Interestingly, BAI1 also mediates Rac-dependent engulfment in professional phagocytes through its interaction with a different Rac1-guanine nucleotide exchange factor module, ELMO/DOCK180. However, this interaction is dispensable for BAI1’s role in synapse development because a BAI1 mutant that cannot interact with ELMO/DOCK180 rescues spine defects in BAI1-knockdown neurons, whereas a mutant that cannot interact with Par3/Tiam1 rescues neither spine defects nor Par3 localization. Further, overexpression of Tiam1 rescues BAI1 knockdown spine phenotypes. These results indicate that BAI1 plays an important role in synaptogenesis that is mechanistically distinct from its role in phagocytosis. Furthermore, our results provide the first example of a cell surface receptor that targets members of the PAR polarity complex to synapses.

BAI1 regulates spatial learning and synaptic plasticity in the hippocampus

“…Synaptic plasticity can be associated with changes in dendritic spine morphology (26). A recent in vitro study suggested that BAI1 interaction with the PAR3/TIAM1 polarity complex regulates spinogenesis in neurons in culture (10). Therefore, we examined whether the aberrant synaptic plasticity in Bai1 -/-mice correlated with alterations in dendritic spine morphology in ex vivo Bai1 -/-hippocampus.…”

“…Brain-specific angiogenesis inhibitor 1 (BAI1) was recently identified as a postsynaptic density (PSD) protein (9,10). BAI1 is a member of the adhesion GPCR subfamily (11), initially identified in a screen for p53-regulated genes (12).…”

The role of G protein-coupled receptors in the early evolution of neurotransmission and the nervous system

“…Adhesion GPCRs are a growing research field, and several of these receptors have shown an important role in the CNS (Araç et al, 2012a; Langenhan et al, 2013;Strokes and Piao, 2010). For example, the brain-specific angiogenesis inhibitor (BAI) subfamily is involved in the control of synaptogenesis (Duman et al, 2013;Stephenson et al, 2014), whereas the latrophilins have been implicated in the control of synaptic transmission (O'Sullivan et al, 2012;O'Sullivan et al, 2014) and GPR56 is associated with brain development (Jeong et al, 2012;Luo et al, 2011;Singer et al, 2013).…”

“…The brain-specific angiogenesis inhibitor family (BAIs; subfamily VII adhesion GPCRs) members are well characterised for their roles in synaptogenesis, involving regulation of synapses and synaptic density (for a review, see Stephenson et al, 2014). Recently, Duman and colleagues provided evidence that BAI1 can regulate synaptogenesis by coupling with Rac1, mediated by a specific interaction and recruitment of the Par3/Tiam1 polarity proteins to postsynaptic sites (Duman et al, 2013). Also, the C-terminal region of BAI1 interacts with PDZ-domain-containing proteins, including MAGI-2 and MAGI-3 (Stephenson et al, 2013).…”

“…Adhesion GPCRs are a growing research field, and several of these receptors have shown an important role in the CNS (Araç et al, 2012a; Langenhan et al, 2013;Strokes and Piao, 2010). For example, the brain-specific angiogenesis inhibitor (BAI) subfamily is involved in the control of synaptogenesis (Duman et al, 2013;Stephenson et al, 2014), whereas the latrophilins have been implicated in the control of synaptic transmission (O'Sullivan et al, 2012;O'Sullivan et al, 2014) and GPR56 is associated with brain development (Jeong et al, 2012;Luo et al, 2011;Singer et al, 2013).GPCRs are well represented in several primitive metazoans, as well as in some pre-metazoan species (de Mendoza et al, 2014; Krishnan et al, 2012;Nordström et al, 2011). Interestingly, several of the pre-bilaterian metazoans, which lack most of the cell types that are commonly found in the bilaterians, still constitute a rich repertoire of GPCRs (Patel, 2012;Technau and Steele, 2011).…”