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.
Highlights
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
We provide evidence that Semaphorin 3A (Sema3A) and its receptor Neuropilin 1 (NRP1) are expressed in the developing gut and that Sema3A exerts a negative control on axonal elongation and synaptic connectivity during ENS maturation
Ganglionated bowel segment from Hirschsprung disease (HSCR) patients, considered by pathologists as the healthy segment, showed a reduced expression of the synaptic molecule synapsin 1, which was inversely correlated with Sema3A expression levels
Summary
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. Enteric neurons and glia are derived from precursors that originate in the neural crest, migrate to the gut, and undergo a complex process of developmental maturation extending to the postnatal period and resulting in functional m aturation[2,3]. The temporal regulation of GDNF expression, together with its diversity of the cellular sources throughout ENS development are thought to underlie the multiple functions attributed to GDNF on neural crest cell migration, neuronal differentiation, neurite extension and synaptogenesis[7,11,18,19]. We determined the expression and distribution of Sema3A and its receptor NRP1 in the rat developing gut and studied the role of Sema3A on neuronal connectivity. Our study identifies Sema3A as a critical regulator of ENS connectivity and provides a putative link between altered ENS connectivity and HSCR
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