Semaphorin 3A controls enteric neuron connectivity and is inversely associated with synapsin 1 expression in Hirschsprung disease

Abstract

Most of the gut functions are controlled by the enteric nervous system (ENS), a complex network of enteric neurons located throughout the wall of the gastrointestinal tract. The formation of ENS connectivity during the perinatal period critically underlies the establishment of gastrointestinal motility, but the factors involved in this maturation process remain poorly characterized. Here, we examined the role of Semaphorin 3A (Sema3A) on ENS maturation and its potential implication in Hirschsprung disease (HSCR), a developmental disorder of the ENS with impaired colonic motility. We found that Sema3A and its receptor Neuropilin 1 (NRP1) are expressed in the rat gut during the early postnatal period. At the cellular level, NRP1 is expressed by enteric neurons, where it is particularly enriched at growth areas of developing axons. Treatment of primary ENS cultures and gut explants with Sema3A restricts axon elongation and synapse formation. Comparison of the ganglionic colon of HSCR patients to the colon of patients with anorectal malformation shows reduced expression of the synaptic molecule synapsin 1 in HSCR, which is inversely correlated with Sema3A expression. Our study identifies Sema3A as a critical regulator of ENS connectivity and provides a link between altered ENS connectivity and HSCR.

The regulation of enteric neuron connectivity by semaphorin 5A is affected by the autism-associated S956G missense mutation

“…With the aim of studying the effects of Sema5A on enteric neuronal connectivity using in vitro ENS culture models, we first validated the expression of Sema5A and PlexinA1/A2 in a widely used ENS culture model derived from embryonic rat gut. 4 , 5 , 22 We found that Sema5A and Plexin A1/A2 were present in neurons, associated with both neuronal cell bodies and axonal processes, but not in glial cells, as observed in rat colon ( Figures 3 A–3C). These results indicated that the cellular expression and distribution of Sema5A and PlexinA1/A2 in ENS in vitro model derived from embryonic rat gut were similar to those in gut tissue.…”

“…The precise mechanisms governing enteric neuronal connectivity as well as molecules involved in these processes remain poorly characterized. However, different classes of molecules, including transcription factors, 2 planar cell polarity pathways, 3 and axonal guidance molecules 4 , 5 have been shown to regulate ENS connectivity.…”

RET enhancer haplotype-dependent remodeling of the human fetal gut development program

“…This group of affected genes contains known neuronal markers like ASCL1, NF1 , and PLXNA2 etc. It is noteworthy that PLXNA2 is a receptor for SEMA3A, whose role in in the migration of enteric neural crest cells is well documented (Anderson, Bergner et al 2007, Gonzales, Le Berre-Scoul et al 2020). Moreover, multiple members of the Semaphorin class 3 genes, including SEMA3A , harbor pathogenic variants in HSCR as well (Luzon-Toro, Fernandez et al 2013, Jiang, Arnold et al 2015).…”

Literature review: enteric nervous system development, genetic and epigenetic regulation in the etiology of Hirschsprung's disease

“…Mutation identified in HSCR cohorts [48,69,70,121] Delays entry of axons and sacral ENCCs into the hindgut. Control neurons connectivity and migration [122,123,124].…”