Hirschsprung Disease and Other Enteric Dysganglionoses

Kapur, Raj P.

doi:10.1080/10408369991239204

Cited by 69 publications

(44 citation statements)

References 277 publications

(275 reference statements)

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“…Failure of ENS precursors to colonize the complete gut results in the absence of enteric ganglia along varying lengths of the colon (colonic aganglionosis) (Newgreen and Young, 2002a;Newgreen and Young, 2002b). This is the most common cause of congenital intestinal obstruction in humans and is clinically referred to as Hirschsprung's disease (HSCR) (Kapur, 1999b;Newgreen and Young, 2002a).…”

Section: Introductionmentioning

confidence: 99%

lessenencodes a zebrafishtrap100required for enteric nervous system development

et al. 2006

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The zebrafish enteric nervous system (ENS), like those of all other vertebrate species, is principally derived from the vagal neural crest. The developmental controls that govern the specification and patterning of the ENS are not well understood. To identify genes required for the formation of the vertebrate ENS, we preformed a genetic screen in zebrafish. We isolated the lessen (lsn) mutation that has a significant reduction in the number of ENS neurons as well as defects in other cranial neural crest derived structures. We show that the lsn gene encodes a zebrafish orthologue of Trap100, one of the subunits of the TRAP/mediator transcriptional regulation complex. A point mutation in trap100 causes a premature stop codon that truncates the protein, causing a loss of function. Antisense-mediated knockdown of trap100 causes an identical phenotype to lsn. During development trap100 is expressed in a dynamic tissue-specific expression pattern consistent with its function in ENS and jaw cartilage development. Analysis of neural crest markers revealed that the initial specification and migration of the neural crest is unaffected in lsn mutants. Phosphohistone H3 immunocytochemistry revealed that there is a significant reduction in proliferation of ENS precursors in lsn mutants. Using cell transplantation studies, we demonstrate that lsn/trap100 acts cell autonomously in the pharyngeal mesendoderm and influences the development of neural crest derived cartilages secondarily. Furthermore, we show that endoderm is essential for ENS development. These studies demonstrate that lsn/trap100 is not required for initial steps of cranial neural crest development and migration, but is essential for later proliferation of ENS precursors in the intestine.

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Section: Introductionmentioning

confidence: 99%

lessenencodes a zebrafishtrap100required for enteric nervous system development

et al. 2006

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“…Seven of the resulting strains are mouse models of Hirschsprung disease. Mutation of six of the genes implicated in distal intestinal aganglionosis in mice is confirmed to cause Hirschsprung disease in humans (11). In addition, we now have several rodent models of abnormal ENS development other than distal intestinal aganglionosis.…”

Section: Molecules Implicated In Control Of Ens Developmentmentioning

confidence: 99%

“…A population-based study documents RET mutations in 3% in individuals with isolated (i.e. nonfamilial) Hirschsprung disease (11,50). Polymorphisms in RET may predispose to Hirschsprung disease in a complex low-penetrance fashion (51).…”

Section: Mash1mentioning

confidence: 99%

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Intestinal Motility Disorders and Development of the Enteric Nervous System

Gariepy

2001

Pediatr Res

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The following article is the third in our series on the developmental biology of the nervous system and its relation to diseases and disorders that are found in newborn infants and children. In this article, Cheryl Gariepy describes the development of the enteric nervous system and the relation between genetic abnormalities of that system and enteric disease. Alvin Zipursky Editor-in-ChiefIntestinal Motility Disorders and Development of the Enteric Nervous System The enteric nervous system (ENS) is an independent nervous system. It contains as many neurons as the spinal cord, every class of neurotransmitter found in the CNS, and reflex arcs capable of functioning independently of CNS input. Whereas the majority of enteric neurons are not directly innervated by the brain or spinal cord, the ENS is in two-way communication with the CNS via parasympathetic and sympathetic neurons. The ENS processes information regarding the state of the intestinal lumen and gut wall and modulates intestinal contractility, secretion, vascular supply, and inflammatory responses (1, 2).Complaints related to the ENS represent a large percentage of pediatric office visits. Common clinical complaints of gastrointestinal motility and sensation include gastroesophageal reflux, dyspeptic syndromes, constipation, chronic recurrent abdominal pain, and irritable bowel syndrome (3). Less common but life-threatening disorders of the ENS include Hirschsprung disease and neuropathic chronic intestinal pseudoobstruction. Our understanding of the pathophysiologic processes underlying these complaints is being aided by the study of ENS formation and structure. Ultimately, these studies will improve our diagnosis and treatment of these disorders.As our understanding of the ENS improves, it becomes very clear that it is no longer sufficient to simply determine whether enteric ganglion cells are present. We are learning the importance of determining whether the correct number and types of ganglion cells are present. This task is complicated by the fact that the morphology of the myenteric plexus varies with location as well as age (4, 5). Only through improved understanding of the normal development of the ENS can we hope to accurately diagnose relatively subtle abnormalities in ENS development (6, 7). Further, with continued basic research, we may be able to isolate an ENS stem cell population from postnatal individuals. The identification and study of multipotential stem cells may allow for their eventual use in transplantation to correct intestinal neuronal deficiencies (8).Recent studies have identified six genes causing Hirschsprung disease, as well as genes that may be related to other disorders of the ENS. This review focuses on studies of ENS development in rodents that have substantially improved our understanding of the genetic basis of human disorders of the ENS. DISCUSSION Origin of the ENSThe ENS is composed of autonomic ganglia in the myenteric and submucosal plexuses and associated connecting neural structures in the bowel wall. The ENS, ...

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“…HD occurs in about one in 5,000 children, and the clinical symptoms included abdominal distension, delayed passage of meconium, and intractable constipation (Furness 2008). The reason for the cause of HD is mainly the interruption of the migration of ectodermal neural crest cells during development, which results in the deficiency of ganglionic cells in the myenteric nerve plexus on distal segment of the intestinal wall (Kapur 1999). Currently, the therapies of HD include the resection and reanastomosis of the intestinal canal.…”

Section: Introductionmentioning

confidence: 99%

Prospective identification and culture of rat enteric neural stem cells (ENSCs)

et al. 2014

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Hirschprung's disease (HD), a very common congenital abnormality in children, occurs mainly due to the congenital developmental defect of the enteric nervous system. The absence of enteric ganglia from the distal gut due to deletion in gut colonization by neural crest progenitor cells may lead to HD. The capacity to identify and isolate the enteric neuronal precursor cells from developing and mature tissues would enable the development of cell replacement therapies for HD. However, a mature method to culture these cells is a challenge. The present study aimed to propose a method to culture enteric neural stem cells (ENSCs) from the DsRed transgenic fetal rat gut. The culture medium used contained 15 % chicken embryo extract, basic fibroblast growth factor, and epidermal growth factor. ENSCs were cultured from embryonic day 18 in DsRed transgenic rat. Under inverted microscope and fluorescence staining, ENSCs proliferated to form small cell clusters on the second day of culture. The neurospheres-like structure were suspended in the medium, and there were some filaments between the adherent cells from day 3 to day 6 of the culture. The neurospheres were formed by ENSCs on day 8 of the culture. Network-like connections were formed between the adherent cells and differentiated cells after adding 10 % FBS. The differentiated cells were positive for neurofilament and glial fibrillary acidic protein antibodies. The present study established a method to isolate and culture ENSCs from E18 DsRed transgenic rats in the terminal stage of embryonic development. This study would offer a way to obtain plenty of cells for the future research on the transplantation of HD.

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Hirschsprung Disease and Other Enteric Dysganglionoses

Cited by 69 publications

References 277 publications

lessenencodes a zebrafishtrap100required for enteric nervous system development

lessenencodes a zebrafishtrap100required for enteric nervous system development

Intestinal Motility Disorders and Development of the Enteric Nervous System

Prospective identification and culture of rat enteric neural stem cells (ENSCs)

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