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

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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Neural crest cell (NCC) receptors and neurotrophins in the developing murine enteric nervous system

Gastroenterology ◽

10.1016/s0016-5085(00)84519-9 ◽

2000 ◽

Vol 118 (4) ◽

pp. A595

Author(s):

Jolanta E. Pitera ◽

Virpi V. Smith ◽

Peter J. Milia

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Neural Crest Cell ◽

Crest Cell

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A second source of precursor cells for the developing enteric nervous system and interstitial cells of Cajal

International Journal of Developmental Neuroscience ◽

10.1016/s0736-5748(02)00103-x ◽

2002 ◽

Vol 20 (8) ◽

pp. 619-626 ◽

Cited By ~ 19

Author(s):

G.S. Sohal ◽

M.M. Ali ◽

F.A. Farooqui

Keyword(s):

Nervous System ◽

Enteric Nervous System ◽

Interstitial Cells Of Cajal ◽

Interstitial Cells ◽

Precursor Cells ◽

Cells Of Cajal

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Distant regulatory elements in a Sox10-βGEO BAC transgene are required for expression ofSox10in the enteric nervous system and other neural crest-derived tissues

Developmental Dynamics ◽

10.1002/dvdy.20769 ◽

2006 ◽

Vol 235 (5) ◽

pp. 1413-1432 ◽

Cited By ~ 48

Author(s):

Karen K. Deal ◽

V. Ashley Cantrell ◽

Ronald L. Chandler ◽

Thomas L. Saunders ◽

Douglas P. Mortlock ◽

...

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Regulatory Elements ◽

Bac Transgene

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Neural crest requires Impdh 2 for development of the enteric nervous system, great vessels, and craniofacial skeleton

Developmental Biology ◽

10.1016/j.ydbio.2015.11.004 ◽

2016 ◽

Vol 409 (1) ◽

pp. 152-165 ◽

Cited By ~ 8

Author(s):

Jonathan I. Lake ◽

Marina Avetisyan ◽

Albert G. Zimmermann ◽

Robert O. Heuckeroth

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Craniofacial Skeleton ◽

Great Vessels

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Neural crest-derived neurons are replaced by a newly identified mesodermal lineage in the post-natal and aging enteric nervous system

10.1101/2020.08.25.262832 ◽

2020 ◽

Author(s):

Subhash Kulkarni ◽

Monalee Saha ◽

Laren Becker ◽

Zhuolun Wang ◽

Guosheng Liu ◽

...

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Dynamic Balance ◽

Intestinal Function ◽

Dominant Form ◽

Prevailing Paradigm ◽

Optimal Balance ◽

Systemic Health ◽

Mesodermal Lineage

ABSTRACTThe enteric nervous system (ENS), a collection of neurons contained in the wall of the gut, is of fundamental importance to gastrointestinal and systemic health. According to the prevailing paradigm, the ENS arises from progenitor cells migrating from the embryonic neural crest and remains largely unchanged thereafter. Here, we show that the composition of maturing ENS changes with time, with a decline in neural-crest derived neurons and their replacement by mesoderm-derived neurons. Single cell transcriptomics and immunochemical approaches establish a distinct expression profile of mesoderm-derived neurons. The dynamic balance between the proportions of neurons from these two different lineages in the post-natal gut is dependent on the availability of their respective trophic signals, GDNF-RET and HGF-MET. With increasing age, the mesoderm-derived neurons become the dominant form of neurons in the ENS, a change associated with significant functional effects on intestinal motility. Normal intestinal function in the adult gastrointestinal tract therefore appears to require an optimal balance between these two distinct lineages within the ENS.

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News from the endothelin-3/EDNRB signaling pathway: Role during enteric nervous system development and involvement in neural crest-associated disorders

Developmental Biology ◽

10.1016/j.ydbio.2018.08.014 ◽

2018 ◽

Vol 444 ◽

pp. S156-S169 ◽

Cited By ~ 8

Author(s):

Nadege Bondurand ◽

Sylvie Dufour ◽

Veronique Pingault

Keyword(s):

Nervous System ◽

Neural Crest ◽

Enteric Nervous System ◽

Signaling Pathway ◽

System Development ◽

Nervous System Development ◽

Endothelin 3 ◽

Enteric Nervous System Development

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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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