Identification and Functional Characterization of a Novel Variant in the SEMA3A Gene in a Chinese Family with Kallmann Syndrome

Figure 4

Mechanism of SEMA3A signaling. The formation of the SEMA3A-NRP-Plexin complex induces the release of FARP2, which can exchange the small G-protein Rac1-GDP to Rac1-GTP. Then, it sequentially activates p21-activated kinase (PAK), LIM kinase 1 (LIMK1), and the actin-binding factor Cofilin, which finally induces actin dynamics and subsequently shifts the balance of Rnd1 and RhoD activity towards this function. Once activated, Plexin can in turn trigger cytoplasmic tyrosine kinases FYN and the serine/threonine kinase CDK5, as well as the collapsin response mediator protein CRMP2, thereby resulting in tubulin dynamics. Activation of plexin-A1 also leads to inactivation of R-RAS, which regulates the function of integrin, resulting in the inactivation of integrin, thereby promoting the separation of target cells and extracellular matrix. SEMA3A can also cause the phosphorylation and dephosphorylation of FAK, thereby activating the downstream Src kinase to achieve the inhibitory effect on integrins. The four pathways mentioned above can eventually cause the growth cone to collapse and ultimately affect the migration of neuronal cells.