scholarly journals Genetic Background Influences Severity of Colonic Aganglionosis and Response to GDNF Enemas in the Holstein Mouse Model of Hirschsprung Disease

2021 ◽  
Vol 22 (23) ◽  
pp. 13140
Author(s):  
Rodolphe Soret ◽  
Nejia Lassoued ◽  
Grégoire Bonnamour ◽  
Guillaume Bernas ◽  
Aurélie Barbe ◽  
...  
Keyword(s):  
Nervous System ◽  
Animal Models ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
Genetic Background ◽  
Positive Impact ◽  
Hirschsprung Disease ◽  
Collagen Vi ◽  
System Defect ◽  
Disease Penetrance

Hirschsprung disease is a congenital malformation where ganglia of the neural crest-derived enteric nervous system are missing over varying lengths of the distal gastrointestinal tract. This complex genetic condition involves both rare and common variants in dozens of genes, many of which have been functionally validated in animal models. Modifier loci present in the genetic background are also believed to influence disease penetrance and severity, but this has not been frequently tested in animal models. Here, we addressed this question using Holstein mice in which aganglionosis is due to excessive deposition of collagen VI around the developing enteric nervous system, thereby allowing us to model trisomy 21-associated Hirschsprung disease. We also asked whether the genetic background might influence the response of Holstein mice to GDNF enemas, which we recently showed to have regenerative properties for the missing enteric nervous system. Compared to Holstein mice in their original FVB/N genetic background, Holstein mice maintained in a C57BL/6N background were found to have a less severe enteric nervous system defect and to be more responsive to GDNF enemas. This change of genetic background had a positive impact on the enteric nervous system only, leaving the neural crest-related pigmentation phenotype of Holstein mice unaffected. Taken together with other similar studies, these results are thus consistent with the notion that the enteric nervous system is more sensitive to genetic background changes than other neural crest derivatives.

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 Roles of Enteric Neural Stem Cell Niche and Enteric Nervous System Development in Hirschsprung Disease

2021 ◽  
Vol 22 (18) ◽  
pp. 9659
Author(s):  
Yue Ji ◽  
Paul Kwong-Hang Tam ◽  
Clara Sze-Man Tang
Keyword(s):  
Nervous System ◽  
Stem Cell ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
Neural Stem Cell ◽  
Stem Cell Niche ◽  
Hirschsprung Disease ◽  
Cell Interaction ◽  
Neural Stem Cell Niche ◽  
Cell Niche

The development of the enteric nervous system (ENS) is highly modulated by the synchronized interaction between the enteric neural crest cells (ENCCs) and the neural stem cell niche comprising the gut microenvironment. Genetic defects dysregulating the cellular behaviour(s) of the ENCCs result in incomplete innervation and hence ENS dysfunction. Hirschsprung disease (HSCR) is a rare complex neurocristopathy in which the enteric neural crest-derived cells fail to colonize the distal colon. In addition to ENS defects, increasing evidence suggests that HSCR patients may have intrinsic defects in the niche impairing the extracellular matrix (ECM)-cell interaction and/or dysregulating the cellular niche factors necessary for controlling stem cell behaviour. The niche defects in patients may compromise the regenerative capacity of the stem cell-based therapy and advocate for drug- and niche-based therapies as complementary therapeutic strategies to alleviate/enhance niche-cell interaction. Here, we provide a summary of the current understandings of the role of the enteric neural stem cell niche in modulating the development of the ENS and in the pathogenesis of HSCR. Deciphering the contribution of the niche to HSCR may provide important implications to the development of regenerative medicine for HSCR.

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

2006 ◽  
Vol 235 (5) ◽  
pp. 1413-1432 ◽  
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

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

2016 ◽  
Vol 409 (1) ◽  
pp. 152-165 ◽  
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

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

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.

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

Development ◽  
2002 ◽  
Vol 129 (12) ◽  
pp. 2785-2796 ◽  
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.

scholarly journals “Too much guts and not enough brains”: (epi)genetic mechanisms and future therapies of Hirschsprung disease — a review

2019 ◽  
Vol 11 (1) ◽  
Author(s):  
Emilie G. Jaroy ◽  
Lourdes Acosta-Jimenez ◽  
Ryo Hotta ◽  
Allan M. Goldstein ◽  
Ragnhild Emblem ◽  
...  
Keyword(s):  
Gene Expression ◽  
Nervous System ◽  
Enteric Nervous System ◽  
Hirschsprung's Disease ◽  
Hirschsprung’S Disease ◽  
Current Knowledge ◽  
Hirschsprung Disease ◽  
Gut Development ◽  
Dna And Rna ◽  
Expression Of Genes

Abstract Hirschsprung disease is a neurocristopathy, characterized by aganglionosis in the distal bowel. It is caused by failure of the enteric nervous system progenitors to migrate, proliferate, and differentiate in the gut. Development of an enteric nervous system is a tightly regulated process. Both the neural crest cells and the surrounding environment are regulated by different genes, signaling pathways, and morphogens. For this process to be successful, the timing of gene expression is crucial. Hence, alterations in expression of genes specific for the enteric nervous system may contribute to the pathogenesis of Hirschsprung’s disease. Several epigenetic mechanisms contribute to regulate gene expression, such as modifications of DNA and RNA, histone modifications, and microRNAs. Here, we review the current knowledge of epigenetic and epitranscriptomic regulation in the development of the enteric nervous system and its potential significance for the pathogenesis of Hirschsprung’s disease. We also discuss possible future therapies and how targeting epigenetic and epitranscriptomic mechanisms may open new avenues for novel treatment.

Sign in / Sign up

Export Citation Format

Share Document