Self-cleavage-dependent and-independent functions of Adgrg1/Gpr56 in mice

• 成果类型: Article
• 署名作者: Kwarcinski, Frank E.; Bernadyn, Tyler F.; Teuber, James P.; Nascimento, Mariane; Bergin, Ingrid; Shen, Tingzhen; Gandhi, Riya; Lu, Xinyi; Brody, Matthew J.; Holinstat, Michael; Tall, Gregory G.
• 署名单位: University of Michigan System; University of Michigan; University of Michigan System; University of Michigan; University of Michigan System; University of Michigan
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.2527832123
• 发表日期: 2026-04-28
• 页码: e2527832123
• 关键词: adhesion GPCRs; brain development; myelination; cardiac development; platelet; protein-coupled receptor; BILATERAL FRONTOPARIETAL POLYMICROGYRIA; tissue transglutaminase; cell-adhesion; GPR56; GPR56/ADGRG1; gpcr

摘要

Adhesion G protein-coupled receptors (AGPCRs) regulate essential physiological processes through interactions between their ectodomains and adjacent cell surface proteins or extracellular matrix components (ECM). AGPCRs distinctively arrive at the plasma membrane as self-cleaved holoreceptors with noncovalently associated N-terminal (NTF) and C-terminal fragments (CTF). Canonical AGPCR signaling proceeds in three sequential steps; NTF adhesive domains bind to ligands, extracellular shear force mediates NTF and CTF dissociation, a tethered peptide agonist (TA) is exposed and binds to the CTF orthosteric site to stabilize the active state receptor. Depending on the cellular context, both autoproteolysis-deficient and perhaps, a few cleavage-capable AGPCRs may be activated without NTF dissociation or the action of the TA. To discriminate the functional consequences of these signaling modes in vivo, we created a cleavage-deficient, Gpr56H381S knock-in mouse and investigated five distinct defective phenotypes of Gpr56knockout mice. One prominent phenotype, brain malformation that parallels human bilateral frontoparietal polymicrogyria (BFPP) disease, is characterized by dysplasia of the cortex and cerebellum and neuron heterotopia. Brain histology analyses confirmed that Gpr56H381S mice had comparable cerebellar structural irregularities as Gpr56knockout mice, indicating that TA agonism is indispensable for proper cerebellar lobule formation and neuronal migration. TA-dependent signaling was also required for male mouse fertility, but not for adult cardiomyocyte homeostatic functions, platelet-dependent hemostasis, or axon myelination in the central nervous system. These findings indicate that GPR56 has multiple modes of activation and that these signaling outcomes are likely driven by NTF interactions with specific ligands including collagen and transglutaminase-2.