Dual roles of Sema6D in cardiac morphogenesis through region-specific association of its receptor, Plexin-A1, with off-track and vascular endothelial growth factor receptor type 2

Abstract

Semaphorins, originally identified as axon guidance factors in the nervous system, play integral roles in organogenesis. Here, we demonstrate a critical involvement of Sema6D in cardiac morphogenesis. Ectopic expression of Sema6D or RNA interference against Sema6D induces expansion or narrowing of the ventricular chamber, respectively, during chick embryonic development. Sema6D also exerts region-specific activities on cardiac explants, a migration-promoting activity on outgrowing cells from the conotruncal segment, and a migration-inhibitory activity on those from the ventricle. Plexin-A1 mediates these activities as the major Sema6D-binding receptor. Plexin-A1 forms a receptor complex with vascular endothelial growth factor receptor type 2 in the conotruncal segment or with Off-track in the ventricle segment; these complexes are responsible for the effects of Sema6D on the respective regions. Thus, the differential association of Plexin-A1 with additional receptor components entitles Sema6D to exert distinct biological activities at adjacent regions. This is crucial for complex cardiac morphogenesis.[Keywords: Semaphorin; Plexin; cardiac development] Supplemental material is available at http://www.genesdev.org.

Altered proliferative ability of neuronal progenitors in PlexinA1 mutant mice

“…Thus, it acts as receptor for Sema6D and forms a complex with the vascular endothelial growth factor receptor 2 (VEGFR2) to convey signals for this semaphorin during cardiac morphogenesis (Toyofuku et al, 2004). Furthermore, a complex formed by Sema3A, Nrp1, and PlexinA1 signaling promotes lymphatic valve formation (Bouvrée et al, 2012).…”

The brain within the tumor: new roles for axon guidance molecules in cancers

“…74 However, at later stages of heart development plexin-A1 acts as a ligand and Sema6D as its receptor. 25 Upon plexin-A1 binding Abl kinase is recruited to the cytoplasmic tail of Sema6D and activated, resulting in phosphorylation of enabled and dissociation from Sema6D. 25 This is the first direct evidence of bi-directional signaling in this system and of a role for semaphorins as receptors.…”

“…25 Upon plexin-A1 binding Abl kinase is recruited to the cytoplasmic tail of Sema6D and activated, resulting in phosphorylation of enabled and dissociation from Sema6D. 25 This is the first direct evidence of bi-directional signaling in this system and of a role for semaphorins as receptors. Other transmembrane semaphorins were also suggested to act as receptors for instance Sema1a and Sema4D, in Drosophila embryo and in immune cells respectively.…”

Regulation of immune cell responses by semaphorins and their receptors

“…For instance, plexin-A1 is associated with the tyrosine kinase receptors off-track and vascular endothelial growth factor receptor 2 in heart morphogenesis. 42 On the other hand, plexin-A1 forms a receptor complex with triggering receptor expressed on myeloid cell (TREM)-2/DNAX-activating protein 12 (DAP12) in osteoclastogenesis. 20 Furthermore, plexin-B1 has been shown to associate with the receptor tyrosine kinases Met and ErbB2, triggering invasive growth of epithelial cells.…”

“…25 Additionally, plexin-A1 serves as a direct binding receptor for class VI semaphorins, Sema6C and Sema6D. 42,57 In the immune system, plexin-A1 is specifically expressed in DCs, where it mediates the activation of T cells and the production of type I interferon. 20,58,59 The generation of antigen-specific T cells is impaired in plexin-A1 2/2 mice.…”