scholarly journals Ret loss-of-function decreases enteric neural crest progenitor proliferation and restricts developmental fate potential during enteric nervous system development

2021 ◽  
Author(s):  
Elizabeth Vincent ◽  
Sumantra Chatterjee ◽  
Gabrielle H Cannon ◽  
Dallas Auer ◽  
Holly Ross ◽  
...  
Keyword(s):  
Nervous System ◽  
Motor Neuron ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
Expression Patterns ◽  
Critical Role ◽  
Nervous System Development ◽  
Developmental Trajectory ◽  
Loss Of Function ◽  
Gi Tract

The receptor tyrosine kinase gene RET plays a critical role in the fate specification of enteric neural crest cells (ENCCs) during enteric nervous system (ENS) development. Ret loss of function (LoF) alleles are associated with Hirschsprung disease (HSCR), which is marked by aganglionosis of the gastrointestinal (GI) tract. ENCCs invade the developing GI tract, proliferate, migrate caudally, and differentiate into all of the major ENS cell types. Although the major phenotypic consequences, and the underlying transcriptional changes from Ret LoF in the developing ENS have been described, its cell type and state-specific effects are unknown. Consequently, we performed single-cell RNA sequencing (scRNA-seq) on an enriched population of ENCCs isolated from the developing GI tract of Ret null heterozygous and homozygous mouse embryos at embryonic day (E)12.5 and E14.5. We demonstrate four significant findings: (1) Ret-expressing ENCCs are a heterogeneous population composed of ENS progenitors as well as glial and neuronal committed cells; (2) neurons committed to a predominantly inhibitory motor neuron developmental trajectory are not produced under Ret LoF, leaving behind a mostly excitatory motor neuron developmental program; (3) HSCR-associated and Ret gene regulatory network genes exhibit distinct expression patterns across Ret-expressing ENCC cells with their expression impacted by Ret LoF; and (4) Ret deficiency leads to precocious differentiation and reduction in the number of proliferating ENS precursors. Our results support a model in which Ret contributes to multiple distinct cellular phenotypes and that Ret LoF contributes to GI aganglionosis in multiple independent ways.

scholarly journals Enteric nervous system development: migration, differentiation, and disease

2013 ◽  
Vol 305 (1) ◽  
pp. G1-G24 ◽  
Author(s):  
Jonathan I. Lake ◽  
Robert O. Heuckeroth
Keyword(s):  
Nervous System ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
System Development ◽  
Hirschsprung Disease ◽  
Nervous System Development ◽  
Receptor Type ◽  
Model Organisms ◽  
Endothelin Receptor ◽  
Type B

The enteric nervous system (ENS) provides the intrinsic innervation of the bowel and is the most neurochemically diverse branch of the peripheral nervous system, consisting of two layers of ganglia and fibers encircling the gastrointestinal tract. The ENS is vital for life and is capable of autonomous regulation of motility and secretion. Developmental studies in model organisms and genetic studies of the most common congenital disease of the ENS, Hirschsprung disease, have provided a detailed understanding of ENS development. The ENS originates in the neural crest, mostly from the vagal levels of the neuraxis, which invades, proliferates, and migrates within the intestinal wall until the entire bowel is colonized with enteric neural crest-derived cells (ENCDCs). After initial migration, the ENS develops further by responding to guidance factors and morphogens that pattern the bowel concentrically, differentiating into glia and neuronal subtypes and wiring together to form a functional nervous system. Molecules controlling this process, including glial cell line-derived neurotrophic factor and its receptor RET, endothelin (ET)-3 and its receptor endothelin receptor type B, and transcription factors such as SOX10 and PHOX2B, are required for ENS development in humans. Important areas of active investigation include mechanisms that guide ENCDC migration, the role and signals downstream of endothelin receptor type B, and control of differentiation, neurochemical coding, and axonal targeting. Recent work also focuses on disease treatment by exploring the natural role of ENS stem cells and investigating potential therapeutic uses. Disease prevention may also be possible by modifying the fetal microenvironment to reduce the penetrance of Hirschsprung disease-causing mutations.

scholarly journals Hoxb3 vagal neural crest-specific enhancer element for controlling enteric nervous system development

2005 ◽  
Vol 233 (2) ◽  
pp. 473-483 ◽  
Author(s):  
Kwok Keung Chan ◽  
Yuk Shan Chen ◽  
Tai On Yau ◽  
Ming Fu ◽  
Vincent Chi Hang Lui ◽  
...  
Keyword(s):  
Nervous System ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
System Development ◽  
Nervous System Development ◽  
Enhancer Element ◽  
Enteric Nervous System Development

scholarly journals Ablation of Ezh2 in neural crest cells leads to aberrant enteric nervous system development in mice

PLoS ONE ◽  
2018 ◽  
Vol 13 (8) ◽  
pp. e0203391
Author(s):  
Hana Kim ◽  
Ingeborg M. Langohr ◽  
Mohammad Faisal ◽  
Margaret McNulty ◽  
Caitlin Thorn ◽  
...  
Keyword(s):  
Nervous System ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
System Development ◽  
Neural Crest Cells ◽  
Nervous System Development ◽  
Enteric Nervous System Development

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

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.

scholarly journals Meis3 is required for neural crest invasion of the gut during zebrafish enteric nervous system development

2015 ◽  
Vol 26 (21) ◽  
pp. 3728-3740 ◽  
Author(s):  
Rosa A. Uribe ◽  
Marianne E. Bronner
Keyword(s):  
Nervous System ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
Molecular Mechanisms ◽  
System Development ◽  
Neural Crest Cells ◽  
Nervous System Development ◽  
Shh Pathway ◽  
Early Migration ◽  
Enteric Nervous System Development

During development, vagal neural crest cells fated to contribute to the enteric nervous system migrate ventrally away from the neural tube toward and along the primitive gut. The molecular mechanisms that regulate their early migration en route to and entry into the gut remain elusive. Here we show that the transcription factor meis3 is expressed along vagal neural crest pathways. Meis3 loss of function results in a reduction in migration efficiency, cell number, and the mitotic activity of neural crest cells in the vicinity of the gut but has no effect on neural crest or gut specification. Later, during enteric nervous system differentiation, Meis3-depleted embryos exhibit colonic aganglionosis, a disorder in which the hindgut is devoid of neurons. Accordingly, the expression of Shh pathway components, previously shown to have a role in the etiology of Hirschsprung’s disease, was misregulated within the gut after loss of Meis3. Taken together, these findings support a model in which Meis3 is required for neural crest proliferation, migration into, and colonization of the gut such that its loss leads to severe defects in enteric nervous system development.

scholarly journals Phosphotyrosine 1062 Is Critical for the In Vivo Activity of the Ret9 Receptor Tyrosine Kinase Isoform

2005 ◽  
Vol 25 (21) ◽  
pp. 9661-9673 ◽  
Author(s):  
Adrianne Wong ◽  
Silvia Bogni ◽  
Pille Kotka ◽  
Esther de Graaff ◽  
Vivette D'Agati ◽  
...  
Keyword(s):  
Nervous System ◽  
Amino Acid ◽  
Tyrosine Kinase ◽  
Enteric Nervous System ◽  
Receptor Tyrosine Kinase ◽  
System Development ◽  
Critical Role ◽  
Nervous System Development ◽  
Binding Motif

ABSTRACT The receptor tyrosine kinase Ret plays a critical role in the development of the mammalian excretory and enteric nervous systems. Differential splicing of the primary Ret transcript results in the generation of two main isoforms, Ret9 and Ret51, whose C-terminal amino acid tails diverge after tyrosine (Y) 1062. Monoisoformic mice expressing only Ret9 develop normally and are healthy and fertile. In contrast, animals expressing only Ret51 have aganglionosis of the distal gut and hypoplastic kidneys. By generating monoisoformic mice in which Y1062 of Ret9 has been mutated to phenylalanine, we demonstrate that this amino acid has a critical role in Ret9 signaling that is necessary for the development of the kidneys and the enteric nervous system. These findings argue that the distinct activities of Ret9 and Ret51 result from the differential regulation of Y1062 by C-terminal flanking sequences. However, a mutation which places Y1062 of Ret51 in a Ret9 context improves only marginally the ability of Ret51 to support renal and enteric nervous system development. Finally, monoisoformic mice expressing a variant of Ret9 in which a C-terminal PDZ-binding motif was mutated develop normally and are healthy. Our studies identify Y1062 as a critical regulator of Ret9 signaling and suggest that Ret51-specific motifs are likely to inhibit the activity of this isoform.

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