Transmembrane semaphorins, forward and reverse signaling: have a look both ways

Abstract

Semaphorins are signaling molecules playing pivotal roles not only as axon guidance cues, but are also involved in the regulation of a range of biological processes, such as immune response, angiogenesis and invasive tumor growth. The main functional receptors for semaphorins are plexins, which are large single-pass transmembrane molecules. Semaphorin signaling through plexins-the "classical" forward signaling-affects cytoskeletal remodeling and integrin-dependent adhesion, consequently influencing cell migration. Intriguingly, semaphorins and plexins can interact not only in trans, but also in cis, leading to differentiated and highly regulated signaling outputs. Moreover, transmembrane semaphorins can also mediate a so-called "reverse" signaling, by acting not as ligands but rather as receptors, and initiate a signaling cascade through their own cytoplasmic domains. Semaphorin reverse signaling has been clearly demonstrated in fruit fly Sema1a, which is required to control motor axon defasciculation and target recognition during neuromuscular development. Sema1a invertebrate semaphorin is most similar to vertebrate class-6 semaphorins, and examples of semaphorin reverse signaling in mammalians have been described for these family members. Reverse signaling is also reported for other vertebrate semaphorin subsets, e.g. class-4 semaphorins, which bear potential PDZ-domain interaction motifs in their cytoplasmic regions. Therefore, thanks to their various signaling abilities, transmembrane semaphorins can play multifaceted roles both in developmental processes and in physiological as well as pathological conditions in the adult.

Keywords: Bidirectional signaling; CNS; Cancer; Heart; Neuron; Retina; Spinal cord.

Fig. 1

Forward and reverse signaling in Drosophila neuromuscular development. a In motor neurons, the interaction of Sema1a with PlexinA—enhanced by perlecan—elicits FAK dephosphorylation and decreased integrin function, resulting in axon defasciculation. This process can be mediated also by Sema1a reverse signaling, through the modulation of Rho activity [17, 18]. b In photoreceptor neurons, Sema1a, acting as PlexinA receptor and interacting with Moesin, inhibits Rho activity, thus enhancing Fas2 adhesive function, resulting in axon fasciculation [20]

Fig. 2

PlexinA2 co-expression suppresses Sema6A-induced repulsion of extending axons in the hippocampus. Sema6A is highly expressed in dendrites of pyramidal neurons of the hippocampus, where it acts in trans as a repellent for extending PlexinA4-expressing axons (mossy fibers). However, Sema6A-mediated repelling signals are attenuated by PlexinA2 co-expression in suprapyramidal CA3 area, allowing mossy fibers to invade this region [29, 30]. This modulatory function of PlexinA2 is only seen in the presence of Sema6A; the homologous semaphorin Sema6B expressed in pyramidal areas is considered a likely alternative repulsive signal, also acting via the PlexinA4 receptor, but independently of PlexinA2 regulation [31]

Fig. 3

In cis interaction between Sema6A and PlexinA2 blocks the repulsive response to Sema6A. During retinal development, Sema6A expressed by starburst amacrine cells of the ON sublamina (represented in orange) acts as a repulsive barrier for amacrine cells expressing PlexinA4 or PlexinA2, constraining their dendrite arborization in the OFF sublamina. However, neural projections of cells within the ON sublamina, characterized by co-expression of Sema6A and PlexinA2, are not sensitive to the repelling activity of the semaphorin [32, 33]

Fig. 4

Sema6A co-expression in cis suppresses PlexinA4 receptor signaling. Sympathetic neurons are repelled by Sema6A, signaling in trans via PlexinA4. By contrast, DRG neurons strongly co-express Sema6A, which forms a complex on the cell surface with its receptor in cis; this impairs PlexinA4 signaling in response to the ligand expressed in other cells. Notably, upon Sema6A knock-out, DRG neurons become responsive to exogenous Sema6A [34]

Fig. 5

In myocardial cells, the Sema6D cytoplasmic tail can bind to Abl and Mena. The interaction with PlexinA1 enhances Abl binding and activation, which results in Mena phosphorylation and dissociation from Sema6D. This removes the inhibitory effect of Mena on cell migration, which is fundamental for heart wall trabeculation [7]