Guidance of myocardial patterning in cardiac development by Sema6D reverse signalling

Abstract

Cardiac chamber formation involves dynamic changes in myocardial organization, including trabeculation and expansion of the compact layer. The positional cues that regulate myocardial patterning, however, remain unclear. Through ligation of the Plexin-A1 receptor, the transmembrane-type semaphorin Sema6D regulates endocardial cell migration. Here, we demonstrate that knockdown of either Sema6D or Plexin-A1 leads to the generation of a small, thin ventricular compact layer and to defective trabeculation. In the heart, expression of the Plexin-A1 extracellular domain alone can rescue the defective trabeculation induced by suppression of Plexin-A1, but not that resulting from defective Sema6D expression. This indicates that reverse signalling by Sema6D occurs within the myocardium. In a ligand-dependent manner, Abl kinase is recruited to the cytoplasmic tail of Sema6D and activated, resulting in phosphorylation of Enabled and dissociation from Sema6D. Constitutive activation of Sema6D signalling enhances the migration of myocardial cells into the trabeculae, whereas inhibition arrests cells within the compact layer. Thus, Sema6D coordinates both compact-layer expansion and trabeculation, functioning as both a ligand and a receptor for Plexin-A1.

Semaphorin 6D regulates the late phase of CD4 + T cell primary immune responses

“…Concomitantly, we also observed a late-phase disruption of CrkL phosphorylation with Sema6D-Ig treatment. Previous studies have reported that Sema6D can activate Abl kinase and that within T cells, Abl regulates phosphorylation of CrkL and LAT but not CD3 (16,20). Given that Sema6D surface protein expression is not enhanced until the late phases of activation, it appears possible that the late-phase inhibition of pLAT may derive directly from a defect in Sema6D signaling by Abl kinase activity.…”

“…These effects of Sema6D-Ig on cell signaling may be explained by two recent reports. The first identified that Sema6D can activate Abl kinase within heart tissue (16). The second demonstrated that within T cells, Abl kinase regulates phosphorylation of LAT but not CD3 (20).…”

“…DCs express Plxna1 along with plexin-A4 (Plxna4), semaphorin 3A (Sema3A), and the coreceptor for Plxna1 and Plxna4, neuropilin-1 (Nrp1) (10,13,14). T cells express Sema3A, semaphorin 6D (Sema6D), and Plxna4 (5,10,(14)(15)(16). These multiple Sema and Plex proteins mediate cell-cell contact between DCs and T cells.…”

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

“…BCR-ABL tyrosine kinase inhibitor, STI571 (imatinib mesylate), was kindly gifted by Novartis Pharmaceuticals (Basel, Switzerland). Expression vectors for p190/ p210BCR-ABL, ABL, STAP-2 and their mutants were described previously Toyofuku et al, 2004;Sekine et al, 2005;Tokunaga et al, 2010). Expression vectors for Myc-tagged-BCR was generated by PCR methods and sequenced (primer sequences are available upon request).…”

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

“…Recent studies in chick embryos have shown that Sema6D is a ligand for plexin-A1 and that their interaction is important for mediating the expansion of the cardiac primordium. 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.…”