De novo enteric neurogenesis in post-embryonic zebrafish from Schwann cell precursors rather than resident cell types

Abstract

The enteric nervous system (ENS) is essential for normal gastrointestinal function. Although the embryonic origin of enteric neurons from the neural crest is well established, conflicting evidence exists regarding postnatal enteric neurogenesis. Here, we address this by examining the origin of de novo neurogenesis in the postembryonic zebrafish ENS. Although new neurons are added during growth and after injury, the larval intestine appears to lack resident neurogenic precursors or classical glia marked by sox10, plp1a, gfap or s100. Rather, lineage tracing with lipophilic dye or inducible Sox10-Cre suggests that post-embryonic enteric neurons arise from trunk neural crest-derived Schwann cell precursors that migrate from the spinal cord into the intestine. Furthermore, the 5-HT 4 receptor agonist prucalopride increases enteric neurogenesis in normal development and after injury. Taken together, the results suggest that despite the lack of resident progenitors in the gut, post-embryonic enteric neurogenesis occurs via gut-extrinsic Schwann cell precursors during development and injury, and is promoted by serotonin receptor agonists. The absence of classical glia in the ENS further suggests that neural crest-derived enteric glia might have evolved after the teleost lineage. This article has an associated 'The people behind the papers' interview.

Zebrafish: A Model Organism for Studying Enteric Nervous System Development and Disease

“…The her4.3 + cells were defined as neural crest derived, post-migratory cells that retain proliferative and neurogenic potential throughout life (McCallum et al, 2020 ). An independent study, also reported the presence of neurogenic precursors in adult zebrafish, that lack expression of the canonical “glial marker” Gfap (El-Nachef and Bronner, 2020 ). They performed lineage tracing and found that these enteric glia were not derived from the vagal neural crest, but from the trunk neural crest, more specifically the Schwann cell precursors (El-Nachef and Bronner, 2020 ).…”

“…The Tg(− 8.3phox2bb :keade) em2tg and Tgbac( phox2bb :eGFP) w37tg reporter lines are frequently used by us and are the most common ones to study the ENS, as they mark all NCCs, including migrating ENCCs and differentiated enteric neurons (Harrison et al, 2014 ; Boer et al, 2016 ) ( Figure 2A ). Alternatively, NCCs and enteric neurons can be labeled using the SAGFF234A gal4 enhancer trap line (Asakawa and Kawakami, 2009 ), whereas the sox10 reporter line labels only early progenitors (El-Nachef and Bronner, 2020 ), and the neural-specific beta tubulin (NBT) promotor labels enteric neurons but not NCCs (Peri and Nusslein-Volhard, 2008 ; Heanue et al, 2016 ). Specific neuronal subsets can also be labeled using neurotransmitter reporter lines, for example the chata reporter line, in which differentiating enteric neurons are labeled (Nikaido et al, 2018 ).…”

Neuron–Glia Interaction in the Developing and Adult Enteric Nervous System

“…Despite opposing results, both studies found similar glial typic markers expressed by their enteric neural precursor cells: p75 NTR , Gfap , S100β , and Sox10 [ 130 ] vs. Nestin , p75 NTR , partially Gfap or S100β but not Sox10 [ 131 ]. Others reported adult neurogenesis to occur in vivo only upon stimulation of the 5-HT receptor and chemical or mechanical injury [ 132 , 133 , 134 , 135 , 136 ]. It remains to be investigated if there exists a difference between normal healthy homeostasis and disease or if it is due to the experimental set-up.…”

“…Generally, ENS formation from NCCs is conserved in higher vertebrates. In zebrafish, new neurons are generated exclusively by SCPs during growth or after injury [ 136 ]. In evolutionary terms, SCPs might be the primary source for enteric neurons [ 139 ].…”

Neuronal lineages derived from the nerve-associated Schwann cell precursors

“…Interestingly, SCP-driven enteric neurogenesis is evident in a postnatal ENS injury model, where SOX10 + cells give rise to the enteric neurons in adult mice during regeneration [ 17 ]. The most recent finding indicates that in post-embryonic zebra fish SCPs associated with the extrinsic gut innervation but not the enteric resident precursor cells are responcible for de novo neurogenesis [ 96 ].…”