Developmental regulation of GDNF response and receptor expression in the enteric nervous system

The development of the enteric nervous system is dependent upon the actions of glial cell line-derived neurotrophic factor (GDNF) on neural crest-derived precursor cells in the embryonic gut. GDNF treatment of cultured enteric precursor cells leads to an increase in the number of neurons that develop and/or survive. Here we demonstrate that, although GDNF promoted an increase in neuron number at all embryonic ages examined, there was a developmental shift from a mitogenic to a trophic response by the developing enteric neurons. The timing of this shift corresponded to developmental changes in gut expression of GFR alpha-1, a co-receptor in the GDNF-Ret signaling complex. GFR alpha-1 was broadly expressed in the gut at early developmental stages, at which times soluble GFR alpha-1 was released into the medium by cultured gut cells. At later times, GFR alpha-1 became restricted to neural crest-derived cells. GFR alpha-1 could participate in GDNF signaling when expressed in cis on the surface of enteric precursor cells, or as a soluble protein. The GDNF-mediated response was greater when cell surface, compared with soluble, GFR alpha-1 was present, with the maximal response seen the presence of both cis and trans forms of GFR alpha-1. In addition to contributing to GDNF signaling, cell-surface GFR alpha-1 modulated the specificity of interactions between GDNF and soluble GFR alphas. These experiments demonstrate that complex, developmentally regulated, signaling interactions contribute to the GDNF-dependent development of enteric neurons.

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In ovo transplantation of enteric nervous system precursors from vagal to sacral neural crest results in extensive hindgut colonisation

Development ◽

10.1242/dev.129.12.2785 ◽

2002 ◽

Vol 129 (12) ◽

pp. 2785-2796 ◽

Cited By ~ 1

Author(s):

Alan J. Burns ◽

Jean-Marie M. Delalande ◽

Nicole M. Le Douarin

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Enteric Neurons ◽

In Ovo ◽

Neuronal Marker ◽

Sacral Region ◽

Enteric Ganglia ◽

Migration Front ◽

Sacral Neural Crest

The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells (NCC). Within the embryonic avian gut, vagal NCC migrate in a rostrocaudal direction to form the majority of neurons and glia along the entire length of the gastrointestinal tract, whereas sacral NCC migrate in an opposing caudorostral direction, initially forming the nerve of Remak, and contribute a smaller number of ENS cells primarily to the distal hindgut. In this study, we have investigated the ability of vagal NCC, transplanted to the sacral region of the neuraxis, to colonise the chick hindgut and form the ENS in an experimentally generated hypoganglionic hindgut in ovo model. Results showed that when the vagal NC was transplanted into the sacral region of the neuraxis, vagal-derived ENS precursors immediately migrated away from the neural tube along characteristic pathways, with numerous cells colonising the gut mesenchyme by embryonic day (E) 4. By E7, the colorectum was extensively colonised by transplanted vagal NCC and the migration front had advanced caudorostrally to the level of the umbilicus. By E10, the stage at which sacral NCC begin to colonise the hindgut in large numbers, myenteric and submucosal plexuses in the hindgut almost entirely composed of transplanted vagal NCC, while the migration front had progressed into the pre-umbilical intestine, midway between the stomach and umbilicus. Immunohistochemical staining with the pan-neuronal marker, ANNA-1, revealed that the transplanted vagal NCC differentiated into enteric neurons, and whole-mount staining with NADPH-diaphorase showed that myenteric and submucosal ganglia formed interconnecting plexuses, similar to control animals. Furthermore, using an anti-RET antibody, widespread immunostaining was observed throughout the ENS, within a subpopulation of sacral NC-derived ENS precursors, and in the majority of transplanted vagal-to-sacral NCC. Our results demonstrate that: (1) a cell autonomous difference exists between the migration/signalling mechanisms used by sacral and vagal NCC, as transplanted vagal cells migrated along pathways normally followed by sacral cells, but did so in much larger numbers, earlier in development; (2) vagal NCC transplanted into the sacral neuraxis extensively colonised the hindgut, migrated in a caudorostral direction, differentiated into neuronal phenotypes, and formed enteric plexuses; (3) RET immunostaining occurred in vagal crest-derived ENS cells, the nerve of Remak and a subpopulation of sacral NCC within hindgut enteric ganglia.

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G protein-coupled receptor trafficking and signaling: new insights into the enteric nervous system

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00406.2018 ◽

2019 ◽

Vol 316 (4) ◽

pp. G446-G452 ◽

Cited By ~ 2

Author(s):

Simona E. Carbone ◽

Nicholas A. Veldhuis ◽

Arisbel B. Gondin ◽

Daniel P. Poole

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

G Protein ◽

Molecular Mechanisms ◽

Intestinal Inflammation ◽

Receptor Expression ◽

Enteric Neurons ◽

Future Research ◽

Detailed Knowledge ◽

G Protein Coupled

G protein-coupled receptors (GPCRs) are essential for the neurogenic control of gastrointestinal (GI) function and are important and emerging therapeutic targets in the gut. Detailed knowledge of both the distribution and functional expression of GPCRs in the enteric nervous system (ENS) is critical toward advancing our understanding of how these receptors contribute to GI function during physiological and pathophysiological states. Equally important, but less well defined, is the complex relationship between receptor expression, ligand binding, signaling, and trafficking within enteric neurons. Neuronal GPCRs are internalized following exposure to agonists and under pathological conditions, such as intestinal inflammation. However, the relationship between the intracellular distribution of GPCRs and their signaling outputs in this setting remains a “black box”. This review will briefly summarize current knowledge of agonist-evoked GPCR trafficking and location-specific signaling in the ENS and identifies key areas where future research could be focused. Greater understanding of the cellular and molecular mechanisms involved in regulating GPCR signaling in the ENS will provide new insights into GI function and may open novel avenues for therapeutic targeting of GPCRs for the treatment of digestive disorders.

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Migration of neural crest-derived enteric nervous system precursor cells to and within the gastrointestinal tract

The International Journal of Developmental Biology ◽

10.1387/ijdb.041935ab ◽

2005 ◽

Vol 49 (2-3) ◽

pp. 143-150 ◽

Cited By ~ 62

Author(s):

Alan J. Burns

Keyword(s):

Nervous System ◽

Gastrointestinal Tract ◽

Neural Crest ◽

Enteric Nervous System ◽

Precursor Cells

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Assessment of protein gene product 9.5 as a marker of neural crest-derived precursor cells in the developing enteric nervous system

Pediatric Surgery International ◽

10.1007/s003830100599 ◽

2001 ◽

Vol 17 (4) ◽

pp. 304-307 ◽

Cited By ~ 24

Author(s):

E. L. Sidebotham ◽

M. N. Woodward ◽

S. E. Kenny ◽

D. A. Lloyd ◽

C. R. Vaillant ◽

...

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Gene Product ◽

Protein Gene ◽

Precursor Cells ◽

Protein Gene Product 9.5 ◽

Protein Gene Product

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Enteric nervous system can regenerate in zebrafish larva via migration into the ablated area and proliferation of neural crest-derived cells

Development ◽

10.1242/dev.195339 ◽

2020 ◽

pp. dev.195339

Author(s):

Maria Ohno ◽

Masataka Nikaido ◽

Natsumi Horiuchi ◽

Koichi Kawakami ◽

Kohei Hatta

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Fluorescent Proteins ◽

Enteric Neurons ◽

Regeneration Process ◽

Congenital Diseases ◽

Zebrafish Larva ◽

Brdu Assay

Enteric nervous system (ENS) which is derived from neural crest is essential for gut function and its deficiency causes severe congenital diseases. Since capacity of ENS regeneration in mammals is limited, additional complimentary models would be useful. Here, we show that the ENS in zebrafish larva at 10-15 days post-fertilization is highly regenerative. The number of enteric neurons (ENs) recovered to ∼50% of the control by 10 days post-ablation (dpa) after their laser ablation. Using transgenic lines in which enteric neural crest-derived cells (ENCDCs) and ENs are labeled with fluorescent proteins, we live-imaged the regeneration process, and found covering by neurites extended from the unablated area and entry of ENCDCs in the ablated areas by 1-3 dpa. BrdU assay suggested that ∼80% of the ENs and ∼90% of the Sox10-positive ENCDCs therein at 7dpa are generated through proliferation. Thus the ENS regeneration involves proliferation, entrance and neurogenesis of ENCDCs. This is the first report regarding the regeneration process of the zebrafish ENS; our findings provide a basis for further in vivo research at single-cell resolution in the vertebrate.

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Dental pulp stem cells as a therapy for congenital entero-neuropathy

10.21203/rs.3.rs-596893/v7 ◽

2021 ◽

Author(s):

Koichiro Yoshimaru ◽

Takayoshi Yamaza ◽

Shunichi Kajioka ◽

Soichiro Sonoda ◽

Yusuke Yanagi ◽

...

Keyword(s):

Stem Cells ◽

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Dental Pulp ◽

Dental Pulp Stem Cells ◽

Enteric Neurons ◽

Deciduous Teeth ◽

Pacemaker Cells ◽

Distal Intestine

Abstract Hirschsprung’s disease is a congenital entero-neuropathy that causes chronic constipation and intestinal obstruction. New treatments for entero-neuropathy are needed because current surgical strategies have limitations5. Entero-neuropathy results from enteric nervous system dysfunction due to incomplete colonization of the distal intestine by neural crest-derived cells. Impaired cooperation between the enteric nervous system and intestinal pacemaker cells may also contribute to entero-neuropathy. Stem cell therapy to repair these multiple defects represents a novel treatment approach. Dental pulp stem cells derived from deciduous teeth (dDPSCs) are multipotent cranial neural crest-derived cells, but it remains unknown whether dDPSCs have potential as a new therapy for entero-neuropathy. Here we show that intravenous transplantation of dDPSCs into the Japanese Fancy-1 mouse, an established model of hypoganglionosis and entero-neuropathy, improves large intestinal structure and function and prolongs survival. Intravenously injected dDPSCs migrate to affected regions of the intestine through interactions between stromal cell-derived factor-1α and C-X-C chemokine receptor type-4. Transplanted dDPSCs differentiate into both pacemaker cells and enteric neurons in the proximal colon to improve electrical and peristaltic activity. Our findings indicate that transplanted dDPSCs can differentiate into different cell types to correct entero-neuropathy-associated defects.

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

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2020.629073 ◽

2021 ◽

Vol 8 ◽

Author(s):

Laura E. Kuil ◽

Rajendra K. Chauhan ◽

William W. Cheng ◽

Robert M. W. Hofstra ◽

Maria M. Alves

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Treatment Options ◽

Model Organism ◽

Nervous System Development ◽

Enteric Neurons ◽

Suitable Model ◽

Large Network

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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