Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color.

Gariepy, Cheryl E.; Cass, Daniel T.; Yanagisawa, Masashi

doi:10.1073/pnas.93.2.867

Cited by 199 publications

(163 citation statements)

References 35 publications

Supporting

Mentioning

156

Contrasting

Unclassified

Order By: Relevance

“…Null mutations of Ednrb in mouse and rat strains show severe aganglionic megacolon due to absence of ganglion cells in the intestine [2,6,7]. However, the s/s mice, in which the expression of Ednrb mRNA was decreased to about 25-27% of the corresponding wild-type levels, only showed pigmented defects without any megacolon symptoms [13].…”

mentioning

confidence: 99%

Anatomic Modifications in the Enteric Nervous System of JF1 Mice with the Classic Piebald Mutation

et al. 2012

View full text Add to dashboard Cite

ABSTRACT. The Japanese Fancy Mouse 1 (JF1) has a characteristic coat color similar to a very old mutant, piebald. The mutation in JF1 and the classic piebald was previously thought to be the same recessive allele in the endothelin B receptor gene (Ednrb) according to the haplotype pattern, which is insufficient for this conclusion. In this study, we identified the same insertion of a retroposon-like element in intron 1 of the Ednrb gene in JF1 as in the classic piebald mutation by PCR. Further, we investigated whether the intestine shows neuronal intestinal malformations such as hypoganglionosis and immaturity of ganglion cells by histochemical staining. Though it has been assumed that the defect of neural crest-derived lineages is restricted to melanocytes in JF1, we found that the enteric innervation and neuronal density were impaired throughout the whole colon in JF1 mice.

show abstract

mentioning

confidence: 99%

Anatomic Modifications in the Enteric Nervous System of JF1 Mice with the Classic Piebald Mutation

et al. 2012

View full text Add to dashboard Cite

show abstract

“…We compared the number of NCSCs in WT and HSCR embryos at different time points in the stomach and small intestine by prospective sorting and retrospectively by culture at clonal density of either dissociated, unselected intestinal cells or selected p75/␣ 4 high cells. The number of stomach and small intestinal cells that express high levels of p75 and ␣ 4 is reduced in HSCR embryos compared with WT after E14.5, with the most dramatic differences occurring at E14.5 and E15.5 ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…At least 10% of human HSCR is cause by defective signaling through endothelin-B receptor (ET B ) (2). The ET Bnull rat is a naturally occurring model of total colonic HSCR (3,4). Postnatally, at least 90% of animals have no ganglion cells beyond the ileocecal junction (3).…”

mentioning

confidence: 99%

Dynamic Changes in the Proximal Gut Neural Crest Stem Cell Population Are Associated with Successful Development of the Distal Enteric Nervous System in Rats

Tsai

Gariepy

2005

Pediatr Res

View full text Add to dashboard Cite

Loss of signaling through the endothelin-B receptor (ET B ) leads to failure of vagal neural crest (NC) cell colonization of the developing gut and causes congenital distal intestinal aganglionosis [Hirschsprung disease (HSCR)] in humans and other mammals. Several studies suggest that cell-cell interactions and the number of NC cells behind the wavefront may play an important role in successful gut colonization. We compared the number and progression of enteric nervous system stem cells in the wild-type (WT) and HSCR rat gut using whole-mount immunohistochemistry for p75, culture and isolation of NC stem cells (NCSCs) by flow cytometry. Isolation and culture demonstrates that NCSCs enter the WT cecum between embryonic day (E) 13.5 and E14.5, and the number of NCSC in the colon significantly increases after E15.5. These findings are consistent with the caudal progression of the NC-cell wavefront by wholemount staining. During the period of WT colonic colonization of the proximal colon, we found significant differences in the small bowel NCSC pool between WT and HSCR rats. Whereas the proximal gut NCSC pool in WT rats is increasing behind the colonization wavefront, no such change occurs in the proximal NCSC pool in HSCR rats. Dynamic changes in the NCSC pool occur behind the NC colonization wavefront in the gut of WT rats. The absence of these changes in the HSCR rat may contribute to distal aganglionosis. Hirschsprung disease (HSCR) is a congenital abnormality of the enteric nervous system (ENS) and is the most common cause of congenital intestinal obstruction. HSCR is characterized by distal intestinal aganglionosis, and current treatment involves resection of the aganglionic segment of bowel. HSCR affects 1 in every 5000 children born worldwide and is associated with a variety of other congenital anomalies and syndromes. Persistent problems with enterocolitis, diarrhea, constipation, or encopresis are common after resection. Rarely, the length of aganglionic bowel is so great that resection leaves insufficient bowel for nutrient absorption. Morbidity and mortality from this disease remain high, even in developed countries (1).All of the neurons and glia of the ENS are derived from the neural crest (NC). The majority of enteric ganglia are derived from vagal NC cells that colonize the developing gut in a cranial-to-caudal progression. HSCR occurs when vagal NC cells fail to complete colonization of the distal gut. Several animal models of HSCR exist, and mutations in eight distinct genes are associated with this developmental abnormality in mammals. At least 10% of human HSCR is cause by defective signaling through endothelin-B receptor (ET B ) (2). The ET Bnull rat is a naturally occurring model of total colonic HSCR (3,4). Postnatally, at least 90% of animals have no ganglion cells beyond the ileocecal junction (3).Several

show abstract

“…The long-studied naturally occurring mutations in mice, piebald lethal and lethal spotting, are mutations in ednrb and edn3, respectively (70,71). In addition, a naturally occurring ednrbnull mutation exists in rats (spotting lethal) (72,73). This mutation leads to total colonic aganglionosis (66,74).…”

Section: Mash1mentioning

confidence: 99%

Intestinal Motility Disorders and Development of the Enteric Nervous System

Gariepy

2001

Pediatr Res

View full text Add to dashboard Cite

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, ...

show abstract

Null mutation of endothelin receptor type B gene in spotting lethal rats causes aganglionic megacolon and white coat color.

Cited by 199 publications

References 35 publications

Anatomic Modifications in the Enteric Nervous System of JF1 Mice with the Classic Piebald Mutation

Anatomic Modifications in the Enteric Nervous System of JF1 Mice with the Classic Piebald Mutation

Dynamic Changes in the Proximal Gut Neural Crest Stem Cell Population Are Associated with Successful Development of the Distal Enteric Nervous System in Rats

Intestinal Motility Disorders and Development of the Enteric Nervous System

Contact Info

Product

Resources

About