Semaphorin 3A is a retrograde cell death signal in developing sympathetic neurons

Abstract

During development of the peripheral nervous system, excess neurons are generated, most of which will be lost by programmed cell death due to a limited supply of neurotrophic factors from their targets. Other environmental factors, such as ‘competition factors' produced by neurons themselves, and axon guidance molecules have also been implicated in developmental cell death. Semaphorin 3A (Sema3A), in addition to its function as a chemorepulsive guidance cue, can also induce death of sensory neurons in vitro. The extent to which Sema3A regulates developmental cell death in vivo, however, is debated. We show that in compartmentalized cultures of rat sympathetic neurons, a Sema3A-initiated apoptosis signal is retrogradely transported from axon terminals to cell bodies to induce cell death. Sema3A-mediated apoptosis utilizes the extrinsic pathway and requires both neuropilin 1 and plexin A3. Sema3A is not retrogradely transported in older, survival factor-independent sympathetic neurons, and is much less effective at inducing apoptosis in these neurons. Importantly, deletion of either neuropilin 1 or plexin A3 significantly reduces developmental cell death in the superior cervical ganglia. Taken together, a Sema3A-initiated apoptotic signaling complex regulates the apoptosis of sympathetic neurons during the period of naturally occurring cell death.

miR-126-5p promotes retinal endothelial cell survival through SetD5 regulation in neurons

“…Sema3A is a secreted protein that mediates its signaling through receptor complexes that include neuropilin 1 and plexin A or D1. Actually, a role for Sema3A as an inducer of cell death has been consistently described in cardiomyocytes (Zhao et al, 2016), tumor (Maione et al, 2009;Moretti et al, 2008), neuronal (Shirvan et al, 2002;Wehner et al, 2016) and endothelial (Guttmann-Raviv et al, 2007) cells, and also in vivo during kidney- (Reidy et al, 2009), tumor- (Maione et al, 2009) and oxygen-induced retinopathy (OIR) (Rivera et al, 2013) development. In the OIR model, microglial cells release IL1β, which induces Sema3A secretion by RGCs and leads to endothelial cell death (Rivera et al, 2013).…”

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

“…Axonal transport is a process whereby cargo and signaling molecules are moved efficiently to and from the MN peripheral axon; it is performed in the retrograde direction by the dynein motor complex (Paschal and Vallee, 1987; Ibáñez, 2007; Zahavi, Maimon and Perlson, 2017). Previous studies have also shown that Sema3A can be internalized and undergoes retrograde transport to the soma (Dang, Smythe and Furley, 2012; Yamashita et al ., 2014; Wehner et al ., 2016). It has also been shown that Sema3A facilitates antero- and retrograde axoplasmic transport of organelles (Goshima et al ., 1997).…”

“…Importantly, inhibiting retrograde transport in the distal axon prevented MN loss in the SOD1 G93A explant (mean fold change over control: Sema3A + Dyn-In 0.92 ± 0.09; control 1 ± 0.04), indicating that Sema3A propagates cell death via a retrograde signaling event. To further determine whether endocytosis of Sema3A components is important for death signaling, as was shown before in different neurons (Wehner et al, 2016), we applied Dynasore, a dynamin-dependent endocytosis inhibitor to the distal axons prior to applying Sema3A, which was shown to internalize via this pathway (Fournier et al ., 2000; Castellani, Falk and Rougon, 2004)(Movie 3-4)(Supplementary Figure 1). Inhibiting Sema3A internalization did not rescue the MNs, and the number of CTX + cells was significantly reduced by ∼30% after 2 days (Figure 1F)(mean fold change over control: Sema3A + Dynasore 0.71 ± 0.01; control 1 ± 0.04).…”

“…Sema3A is a secreted protein that was initially identified because of its ability to induce the collapse and paralysis of axonal growth cones of chick sensory neurons in vitro (Luo, Raible and Raper, 1993). However, Sema3A has also been shown to induce neuronal cell death via several mechanisms (Nakamura, Kalb and Strittmatter, 2000; de Wit et al ., 2006; Ben-Zvi et al ., 2008; Yamashita et al ., 2014; Wehner et al ., 2016) and to be involved in a variety of pathologies in adults, including ALS (Good et al ., 2004; De Winter et al ., 2006; Venkova et al ., 2014; Maimon et al ., 2018). Collapsin Response Mediator Proteins (CRMPs) constitute a family well known for their intracellular response to Sema3A-Plexin binding.…”

The Role of Apoptotic Signaling in Axon Guidance

“…Emerging evidence reveals that repellent signaling pathways are able to activate caspases, in some cases through direct binding. The Slit/Robo, Eph/Ephrin and Sema/Plexin pathways all recruit and/or activate caspases [17,66,[77][78][79][80][81]. Slit/Robo signaling in zebrafish axons has been shown to genetically interact with caspases, in a manner that suggests localized activation [66].…”