The role and mechanism-of-action of Sema3E and Plexin-D1 in vascular and neural development

Abstract

Class 3 secreted semaphorins (Sema3A to 3F) participate in many aspects of axon guidance through holoreceptor complexes that include Neuropilin-1 (Npn-1) or Neuropilin-2 and one of the four class A plexin proteins. However, unlike other Sema3 family proteins, Sema3E directly binds to Plexin-D1 without neuropilins. Its biological function was first explored in intersomitic vessel formation and since its initial discovery, Sema3E-Plexin-D1 signaling has been found to participate in the many biological systems in addition to vascular development, via seemingly different mode of actions. For example, temporal and spatial control of ligand vs. receptor results in two different mechanisms governing vascular patterning. Interactions with other transmembrane proteins such as neuropilin or VEGFR2 results in different axonal behaviors. Ligand receptor localization on pre- vs. post-synaptic neurons is used to control different types of synapse formation. Perhaps different downstream effectors will also result in different functional outcomes. Given the limited number of ligands and receptors in the genome and their multifunctional nature, we expect that more modes of action will be discovered in the future. In this review, we highlight current advances on the mechanisms of how Sema3E-Plexin-D1 interaction shapes the networks of multiple biological systems, in particular the vascular and nervous systems.

Semaphorins in cardiovascular medicine

“…These results have been confirmed in Sema3a À/À mice (reviewed in [41]). A similar phenotype is described in both Plexin-d1 À/À and Sema-3e À/À mice, in which the intersomitic vessels are not excluded from the caudal region where SEMA3E is expressed and the vessels extend ectopically through the somites [42].…”

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

“…These studies identified SEMA3E as a novel neurotrophic factor that signals via PLXND1 and KDR to activate prosurvival signaling in GnRH neurons. This function differs significantly from previously known roles for SEMA3E in modulating the cytoskeleton during vascular and axon guidance (44). Moreover, the functional importance of SEMA3E for neuron survival is fundamentally different from that of SEMA3A, which is mutated in other KS patients (7), but causes the ectopic migration of GnRH neurons along mispatterned axons in the nose (5).…”

Homozygous HOXB1 loss‐of‐function mutation in a large family with hereditary congenital facial paresis

“…PLXND1 is a member of the plexin protein family which bind to semaphorins and regulate neuronal migration [Oh and Gu, 2013]. REV3L is the catalytic subunit of DNA polymerase zeta required for mutagenic replication of damaged DNA [Makarova and Burgers, 2015].…”