The adhesion-GPCR BAI1 shapes dendritic arbors via Bcr-mediated RhoA activation causing late growth arrest

Abstract

Dendritic arbor architecture profoundly impacts neuronal connectivity and function, and aberrant dendritic morphology characterizes neuropsychiatric disorders. Here, we identify the adhesion-GPCR BAI1 as an important regulator of dendritic arborization. BAI1 loss from mouse or rat hippocampal neurons causes dendritic hypertrophy, whereas BAI1 overexpression precipitates dendrite retraction. These defects specifically manifest as dendrites transition from growth to stability. BAI1-mediated growth arrest is independent of its Rac1-dependent synaptogenic function. Instead, BAI1 couples to the small GTPase RhoA, driving late RhoA activation in dendrites coincident with growth arrest. BAI1 loss lowers RhoA activation and uncouples it from dendrite dynamics, causing overgrowth. None of BAI1’s known downstream effectors mediates BAI1-dependent growth arrest. Rather, BAI1 associates with the Rho-GTPase regulatory protein Bcr late in development and stimulates its cryptic RhoA-GEF activity, which functions together with its Rac1-GAP activity to terminate arborization. Our results reveal a late-acting signaling pathway mediating a key transition in dendrite development.

Mechanisms of adhesion G protein–coupled receptor activation

“…This could activate the receptor by relieving repression conferred by the NTF or by utilizing the CTF stalk as a fulcrum in a manner akin to class C receptors that use a rigid body to impart activating conformational changes to the 7TM. ADGRB receptors are enriched in the post-synapse and bind secreted C1q-like proteins and an unknown trans-synaptic ligand (possibly the peripheral membrane-associated RTN4R) to regulate synapse formation and maintenance via the thrombospondin-like repeat (TSR) domains (46,142,182). ADGRL is also enriched in the post-synapse and interacts with both FLRT and Teneurin (TEN) single-pass receptors simultaneously to form trans-synaptic links that promote synaptogenesis (78)(79)(80).…”

Novel phospho-switch function of delta-catenin in dendrite development

“…The Rho family of small GTPases has extensive roles in neurite development and maintenance via cytoskeletal remodeling ( Govek et al, 2005 ). RhoA activity inhibits dendritic branching in hippocampal neurons, with a recent study involving a G protein–coupled receptor (BAI1) reporting that dendritic RhoA activity normally increases in later stages of dendrite growth as a means to terminate arborization ( Nakayama et al, 2000 ; Duman et al, 2019 ). Conversely, delta-catenin has been reported to inhibit RhoA activity via the sequestration of a RhoA activator (p190RhoGEF), enhancing dendrite arborization and growth ( Kim et al, 2008a ).…”

Mutations in G Protein–Coupled Receptors: Mechanisms, Pathophysiology and Potential Therapeutic Approaches

“…Adhesion GPCRs are not only capable of cis-signaling (e.g., G-protein activation) but also function as a signal for other receptors (transsignaling) (Liebscher et al, 2013). It has been shown in Caenorhabditis elegans and mouse that phenotypes caused by complete aGPCR gene knockouts can be partially rescued only by a membrane-anchored N terminus (Prömel et al, 2012;Patra et al, 2013;Duman et al, 2019), indicating 7TMD-independent functions of the N terminus. Indeed, transcript analyses determined that the domain architecture of the N terminus of aGPCRs often differs, and N termini without or with an incomplete 7TMD anchor as well as separate 7TMD are frequently derived from a single aGPCR gene (Knierim et al, 2019).…”