Glial Cell-Derived Neurotrophic Factor Induces Enteric Neurogenesis and Improves Colon Structure and Function in Mouse Models of Hirschsprung Disease

Soret, Rodolphe; Schneider, Sabine; Bernas, Guillaume; Christophers, Briana; Souchkova, Ouliana; Charrier, Baptiste; Righini-Grunder, Franziska; Aspirot, Ann; Landry, Mathieu; Kembel, Steven W.; Fauré, Christophe; Heuckeroth, Robert O.; Pilon, Nicolas

doi:10.1053/j.gastro.2020.07.018

Cited by 67 publications

(69 citation statements)

References 52 publications

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“…Regenerative medicine and trophic factor modulation hold promise for treating life-threatening enteric neuropathies. 2 , 3 To facilitate reprogramming and improve bowel function, better understanding of the molecular identity and characteristics of ENS subtypes is needed. 2 We used single-cell transcriptomics to identify hundreds of neurotransmitters, receptors, ion channels, signaling molecules, and messenger RNA regulatory genes differentially expressed in 7 mouse myenteric neuron subclasses in adult distal colon and 8 neuron groups at E17.5.…”

Section: Discussionmentioning

confidence: 99%

“…Unfortunately, we have limited ability to identify missing or defective ENS cell populations in people with bowel dysmotility, and therapies are inadequate. Promising new approaches like regenerative medicine 2 or glial cell line–derived neurotrophic factor (GDNF)–induced regeneration of the ENS 3 would benefit from a more thorough characterization of the transcription factors, receptors, and signaling pathways that define enteric neuron subclasses.…”

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confidence: 99%

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scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3

Wright

Schneider

Smith‐Edwards

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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113

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Background and Aims Bowel function requires coordinated activity of diverse enteric neuron subtypes. Our aim was to define gene expression in these neuron subtypes to facilitate development of novel therapeutic approaches to treat devastating enteric neuropathies, and to learn more about enteric nervous system function. Methods To identify subtype–specific genes, we performed single-nucleus RNA-seq on adult mouse and human colon myenteric plexus, and single-cell RNA-seq on E17.5 mouse ENS cells from whole bowel. We used immunohistochemistry, select mutant mice, and calcium imaging to validate and extend results. Results RNA-seq on 635 adult mouse colon myenteric neurons and 707 E17.5 neurons from whole bowel defined seven adult neuron subtypes, eight E17.5 neuron subtypes and hundreds of differentially expressed genes. Manually dissected human colon myenteric plexus yielded RNA-seq data from 48 neurons, 3798 glia, 5568 smooth muscle, 377 interstitial cells of Cajal, and 2153 macrophages. Immunohistochemistry demonstrated differential expression for BNC2, PBX3, SATB1, RBFOX1, TBX2, and TBX3 in enteric neuron subtypes. Conditional Tbx3 loss reduced NOS1-expressing myenteric neurons. Differential Gfra1 and Gfra2 expression coupled with calcium imaging revealed that GDNF and neurturin acutely and differentially regulate activity of ∼50% of myenteric neurons with distinct effects on smooth muscle contractions. Conclusion Single cell analyses defined genes differentially expressed in myenteric neuron subtypes and new roles for TBX3, GDNF and NRTN. These data facilitate molecular diagnostic studies and novel therapeutics for bowel motility disorders.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3

Wright

Schneider

Smith‐Edwards

et al. 2021

Cellular and Molecular Gastroenterology and Hepatology

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113

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“…Similarly, we demonstrated increased NCC survival and growth in a chemically induced HSCR rat model, by using a ROCK inhibitor (Zhao et al, 2020). Another study found that administration of glial cell derived neurotrophic factor (GDNF) rescued megacolon, prevented death and stimulated ENS regeneration in the Holstein (a model for trisomy 21associated HSCR), TashT (a model for male-biased HSCR) and Piebald-lethal (a model for EDNRB mutation-associated HSCR) mice models (Soret et al, 2020). These results suggest that factors expressed by cells other than enteric neurons, are able to promote proliferation and engraftment of ENCCs.…”

Section: Identification Of Drugs That Stimulate Ens Developmentmentioning

confidence: 96%

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

Kuil¹,

Chauhan²,

Cheng³

et al. 2021

Front. Cell Dev. Biol.

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The Enteric Nervous System (ENS) is a large network of enteric neurons and glia that regulates various processes in the gastrointestinal tract including motility, local blood flow, mucosal transport and secretion. The ENS is derived from stem cells coming from the neural crest that migrate into and along the primitive gut. Defects in ENS establishment cause enteric neuropathies, including Hirschsprung disease (HSCR), which is characterized by an absence of enteric neural crest cells in the distal part of the colon. In this review, we discuss the use of zebrafish as a model organism to study the development of the ENS. The accessibility of the rapidly developing gut in zebrafish embryos and larvae, enables in vivo visualization of ENS development, peristalsis and gut transit. These properties make the zebrafish a highly suitable model to bring new insights into ENS development, as well as in HSCR pathogenesis. Zebrafish have already proven fruitful in studying ENS functionality and in the validation of novel HSCR risk genes. With the rapid advancements in gene editing techniques and their unique properties, research using zebrafish as a disease model, will further increase our understanding on the genetics underlying HSCR, as well as possible treatment options for this disease.

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“…2F), ruling out the possibility that our vDAO preparation might have contained another substance with anti-histamine activity. Moreover, the muscle relaxing activity of vDAO seems to be specific for histamine-induced contractions as vDAO had no impact on L-NAME-provoked 43 muscle contractions ( Fig. S1).…”

Section: Resultsmentioning

confidence: 98%

Vegetal diamine oxidase alleviates histamine-induced contraction of colonic muscles

Nerée

Soret

Marcocci

et al. 2020

Sci Rep

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Excess of histamine in gut lumen generates a pronounced gastrointestinal discomfort, which may include diarrhea and peristalsis dysfunctions. Deleterious effects of histamine can be alleviated with antihistamine drugs targeting histamine receptors. However, many antihistamine agents come with various undesirable side effects. Vegetal diamine oxidase (vDAO) might be a relevant alternative owing to its histaminase activity. Mammalian intestinal mucosa contains an endogenous DAO, yet possessing lower activity compared to that of vDAO preparation. Moreover, in several pathological conditions such as inflammatory bowel disease and irritable bowel syndrome, this endogenous DAO enzyme can be lost or inactivated. Here, we tested the therapeutic potential of vDAO by focusing on the well-known effect of histamine on gut motility. Using ex vivo and in vitro assays, we found that vDAO is more potent than commercial anti-histamine drugs at inhibiting histamine-induced contraction of murine distal colon muscles. We also identified pyridoxal 5′-phosphate (the biologically active form of vitamin B6) as an effective enhancer of vDAO antispasmodic activity. Furthermore, we discovered that rectally administered vDAO can be retained on gut mucosa and remain active. These observations make administration of vDAO in the gut lumen a valid alternative treatment for histamine-induced intestinal dysfunctions.

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Glial Cell-Derived Neurotrophic Factor Induces Enteric Neurogenesis and Improves Colon Structure and Function in Mouse Models of Hirschsprung Disease

Cited by 67 publications

References 52 publications

scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3

scRNA-Seq Reveals New Enteric Nervous System Roles for GDNF, NRTN, and TBX3

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

Vegetal diamine oxidase alleviates histamine-induced contraction of colonic muscles

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