Semaphorin Signaling in Neurons

Semaphorins are a family of growth cone guidance molecules conserved from insects to mammals that are implicated in mediating repulsive guidance during neurodevelopment and neuronal regeneration. The range of neurons responsive to semaphorins is extensive and includes dorsal root ganglion, sympathetic, motor, cerebellar, hippocampal, olfactory and corticospinal neurons. Currently, more than 20 members have been identified and they all share a conserved, 500 amino acid residue Sema domain near their amino terminus. Semaphorins are divided into eight classes according to species of origin and structural similarities. The best characterized class of the semaphorin family is the Class 3 semaphorin group. Currently, six members have been identified (Sema3A-F), which have been implicated in cell migration, tumor growth and immune response.

Repulsive signals elicited by semaphorins are exerted by two receptor families: neuropilins (Nrp1 and Nrp2), and plexins (PlxnA1-4, PlxnB1-3, PlxnC1, and PlxnD1). Many semaphorins bind directly to plexins and activate cytoplasmic signaling cascades. The well-characterized Class 3 semaphorins require Nrp1-PlxnA1 complex as the functional receptor. Sema3A binds only to Nrp1. In contrast, Sema3B, Sema3C and Sema3F bind to both Nrp1 and Nrp2. They function as agonists at Nrp2 sites on sympathetic neurons and as antagonists of Nrp1 sites on dorsal root ganglion. The transmembrane and cytoplasmic domains are not required for semaphorin signaling through Nrp1. At least two signaling pathways are involved in the response to Sema3A. One includes the small GTPase Rac1 and leads to the depolymerization of actin filaments. A second leads to the loss of integrin-mediated substrate adhesion. PlxnA1 binds the Rho-family GTPases Rnd1 and RhoD which have antagonistic effects on PlxnA1 and are likely involved in the initiation or modulation, but not the execution of, cytoskeletal collapse by PlxnA1. They act upstream of PlxnA1 to regulate its activity as a Sema3A receptor. Activation of the Nrp1/PlxnA1 receptor complex by Sema3A also stimulates phosphorylation of cofilin. Phosphorylation of Cofilin by LIMK downregulates cofilin's ability to promote actin filament turnover. In addition to Rho-family GTPases, plexins directly and indirectly interact with several other molecules including the kinases Fes, Fyn, ROCK and CDK5, and the CRMP proteins. Fes directly interacts with the CRMP/CRAMS complex, which has a role in the regulation of actin polymerization and microtubule dynamics. CRMP can bind tubulin directly and this provides a connection between axon guidance and microtubule organization in a region of the growth cone that lies behind the actin-rich region. Fyn is also implicated in PlxnA signaling. CDK5 binds to PlxnA2. Rac can interact with PlxnB, but not with PlxnA or PlxnC, and PlxnB suppresses Rac function by competing with other Rac downstream targets such as PAK. Sema4D stimulates RhoA activation by a direct interaction between PlxnB, RhoGEF and LARG. In addition, Sema4D triggers the invasive growth of epithelial cells, including cell-cell dissociation, anchorage-independent growth, and branching morphogenesis by binding to the PlxnB1-Met complex. Binding of Sema4D to PlxnB1 stimulates the intrinsic tyrosine kinase activity of Met, leading to the phosphorylation of both the receptor and the Met substrate GAB1. Sema7A does not signal through neuropilins or plexins. Instead, its signaling seems to be mediated by the binding to integrins, which activate ERKs and FAK. Although semaphorins and their receptors are recognized for their roles in axon guidance, they are also expressed in various non-neuronal organs and tissues such as the heart, bone, kidney, intestine, and lung. They act in lung development, angiogenesis, hematopoiesis, and endocrine regulation.