as a structural PDZ interaction motif on its C-terminus. C-class plexins have fewer structural Methionine-Related Sequences (MRS) and IPT domains. D-class plexins have an additional modification in one of the MRS domains Function Plexin receptors largely act to signal the binding of semaphorin signaling proteins in a short-distance inhibitory manner. Each class of plexin has a range of specificity, meaning they could bind specifically to one or more semaphorin isomers. Plexins also have varying effects on development depending on their expression in different tissue types. Plexin receptors have implications in neural development and axon growth guidance, angiogenesis and heart development, skeletal and kidney morphogenesis, and in the immune system. Genetic knockout of plexins have shown to be lethal at embryonic stages due to severe developmental defects in body systems regulated by semaphorin-plexin signaling. Malfunction of the plexin signaling pathway has been implicated in human diseases including neurological disorders and cancers. Axon guidance Plexin receptors on axon growth cones receive local semaphorin signaling and impede growth in that direction. Plexin activation on growth cones results in actin and microtubule polymer destabilization as well as clathrin-mediated endocytosis, resulting in retraction of growth cone projections. Angiogenesis and heart development PLXND1 is involved in guiding the growth of new blood vessels. Cells expressing Sema3E do not need additional vascularization. Developing vessels will have their growth towards these cells inhibited upon PLXND1 binding to Sema3E independent of Neuropilin. PLXNA2 and PLXND1 modulate proper development of cardiac structures. Skeletal and kidney development During development, PLXNA1 and PLXNA2 are expressed in chondrocytes and osteoblasts, implementing them in regulating bone homeostasis. PLXND1 has a role in the formation of vertebral bodies of the spinal column by signaling for proper fusing and splitting of the axial elements. PLXNB1 and PLXNB2 control branching of the ureter in the kidney by inhibiting and promoting it, respectively. Immune system PLXNA1 promotes dendritic and T cell proliferation. PLXNA4 inhibits T cell response, but promotes inflammatory cytokine production by macrophages. PLXNB1 promotes B cell survival, as well as macrophage recruitment. Role in intelligence In a genome-wide association study, plexins, which are mutated in several monogenic neurodevelopmental disorders, were significantly enriched for associations with high IQ. References Single-pass transmembrane proteins