Enteric glia as a source of neural progenitors in adult zebrafish

Abstract

The presence and identity of neural progenitors in the enteric nervous system (ENS) of vertebrates is a matter of intense debate. Here, we demonstrate that the non-neuronal ENS cell compartment of teleosts shares molecular and morphological characteristics with mammalian enteric glia but cannot be identified by the expression of canonical glial markers. However, unlike their mammalian counterparts, which are generally quiescent and do not undergo neuronal differentiation during homeostasis, we show that a relatively high proportion of zebrafish enteric glia proliferate under physiological conditions giving rise to progeny that differentiate into enteric neurons. We also provide evidence that, similar to brain neural stem cells, the activation and neuronal differentiation of enteric glia are regulated by Notch signalling. Our experiments reveal remarkable similarities between enteric glia and brain neural stem cells in teleosts and open new possibilities for use of mammalian enteric glia as a potential source of neurons to restore the activity of intestinal neural circuits compromised by injury or disease.

Notch signaling drives development of Barrett’s metaplasia from Dclk1-positive epithelial tuft cells in the murine gastric mucosa

“…In light of the substantial mutational load described in BE tissues 46 , the chronic inflammatory environment of the pL2 mouse model combined with increased Notch signaling may thus suffice to induce oncogenic growth from Dclk1-positive tuft cells. Lastly, Dclk1 is also expressed in cells of the enteric nervous system (ENS) 21 , 47 , and modulations of Notch signaling in cells of the ENS may result in an altered glial and neuronal differentiation 48 , 49 and contribute to the epithelial phenotype.…”

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

“…The authors also showed zebrafish Glial fibrillary acidic protein (Gfap) immunohistochemistry staining where, enteric glia processes largely form an inner layer separating neuronal axons from the intestinal epithelium (Baker et al, 2019 ). However, another report states that the observed Gfap staining likely represents cross-reactivity, as it persisted in ret mutant larvae lacking an ENS (McCallum et al, 2020 ). Moreover, they show that zebrafish enteric glia do not seem to (highly) express the canonical “glial markers” such as, the fatty acid binding protein 7 (Fabp7) and the S100 calcium-binding protein B (s100β).…”

“…They also show that, zebrafish enteric glia resemble mammalian enteric glia based on their ultrastructural and general morphology, gene expression and location. 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). Thus, although zebrafish enteric glia do not express the canonical "glial markers" and Gfap immunohistochemistry might be unspecific for enteric glia in zebrafish, a neurogenic progenitor population with enteric glial characteristics seems to exist in this organism, opening new avenues to study these progenitor cells and explore whether they remain present in HSCR models (El-Nachef and Bronner, 2020;McCallum et al, 2020).…”

ZEB2, the Mowat-Wilson Syndrome Transcription Factor: Confirmations, Novel Functions, and Continuing Surprises

“…Taken together, ZEB2-co-controlled astrocyte activation and reactive gliosis, including in a context of multicellular responses (including microglia; [ 188 ]) to nervous system damage and disease, is an exciting new ZEB2 research line to explore in mouse and zebrafish models for (repetitive) injuries and pathologies of the brain [ 189 ], spinal cord [ 190 ], retina [ 191 ] and ENS [ 192 , 193 ], and perhaps, more speculative, also in blood vessel disease caused by endothelial dysfunction, e.g., in the brain and in neuroretinal degeneration [ 194 ].…”