Genetic Background Strongly Modifies the Severity of Symptoms of Hirschsprung Disease, but Not Hearing Loss in Rats Carrying Ednrbsl Mutations

Dang, Ruihua; Torigoe, Daisuke; Suzuki, Sari; Kikkawa, Yoshiaki; Moritoh, Kanako; Sasaki, Nobuya; Agui, Takashi

doi:10.1371/journal.pone.0024086

Cited by 37 publications

(48 citation statements)

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“…In a previous study, we reported that there are resistant loci to aganglionosis in the genetic background of the F344 strain [3]. Despite the decrease in the expression level of the Ednrb gene and hypoganglionosis, JF1 mice do not show any megacolon symptoms (n=150).…”

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

et al. 2012

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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.

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

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“…The genetic background of inbred rodents also has important effects on ENS morphogenesis and disease phenotypes (Dang et al, 2011; Walters et al, 2010). This observation suggests that in outbred human populations there may also be diverse and unpredictable responses to cell transplantation because of unknown genetic modifier effects.…”

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confidence: 99%

White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies

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et al. 2016

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Over the last 20 years, there has been increasing focus on the development of novel stem cell based therapies for the treatment of disorders and diseases affecting the enteric nervous system (ENS) of the gastrointestinal tract (so-called enteric neuropathies). Here, the idea is that ENS progenitor/stem cells could be transplanted into the gut wall to replace the damaged or absent neurons and glia of the ENS. This White Paper sets out experts’ views on the commonly used methods and approaches to identify, isolate, purify, expand and optimize ENS stem cells, transplant them into the bowel, and assess transplant success, including restoration of gut function. We also highlight obstacles that must be overcome in order to progress from successful preclinical studies in animal models to ENS stem cell therapies in the clinic.

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“…When bred onto two different genetic backgrounds, these features were differently modified. Among three strains of homologous rats, the AGH-mutant rats showed the most serious aganglionosis, followed by the LEH and F344 mutants, which corresponded to the order of their average survival time (5). Thus, we concluded that variations in penetrance and survival period among the three strains of Ednrb sl/sl rats were attributable to distinct differences in the severity of aganglionosis, and modifier genes in the genetic backgrounds of these strains significantly modulated the severity of the aganglionosis phenotype.…”

Section: Table 1 Peripheral White Blood Cells (Wbc) Red Blood Cells mentioning

confidence: 75%

“…We found that genetic background strongly modified the symptoms of aganglionosis but not hearing loss (5). In this study, we also investigated the impact of genet- cell counts in the mutant animals.…”

Section: Table 1 Peripheral White Blood Cells (Wbc) Red Blood Cells mentioning

confidence: 92%

“…Next, to assess the abnormality of the blood in AGH strains, the mutant and wildtype rats were examined for peripheral red blood cells, white blood cells, platelets, hematocrit and hemoglobin levels. Table 1 shows a significant decrease in white blood notyping of the Ednrb alleles in AGH/Hkv-Ednrb, LEH/Hkv-Ednrb and F344-Ednrb rats was performed as described previously (5). All research and experimental protocols were conducted according to the Regulation for the Care and Use of Laboratory Animals of Hokkaido University (Approval ID: No.…”

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Lymphopenia in Ednrb-deficient rat was strongly modified by genetic background

et al. 2012

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The endothelin signaling pathway plays an important role in the migration, proliferation, and differentiation of neural crest cells. Mutations in the gene encoding the endothelin receptor type B (EDNRB) cause three symptoms: aganglionosis, pigmented disorder and hearing loss. In addition, the Ednrb null mice show abnormal splenic microarchitecture with lymphopenia. In this study, we examined whether similar phenotypes are reproduced in three Ednrb-null rat strains that we established previously. AGH-Ednrb sl/sl strain showed a low white blood cell count, significant size reduction and abnormal microarchitecture of spleen. Thymus displayed a marked reduction in the size, but maintained a normal CD4/CD8 ratio. In contrast, splenic cellularity was reduced to < 15%, and splenic B and T cell numbers were reduced, showing a splenic lymphopenia. Interestingly, Ednrb-null rats in the LE and F344 genetic background did not show these abnormalities. These data show that proper T and B cell development is dependent on the endothelin signaling pathway, however, modifier gene(s) might be differentially expressed in these strain to modulate or compensate for the effect of the Ednrb deficiency.The endothelin receptor type B (EDNRB) is a G protein-coupled receptor that activates a phosphatidylinositol-calcium second messenger system. The receptor interacts with a family of ligands known as endothelins to regulate several critical biological processes, including the development and function of blood vessels, the production of certain hormones, and the stimulation of cell growth and division (9). Endothelin 3 is one of the proteins that interacts with EDNRB. During embryonic development, endothelin 3/EDNRB interaction plays an important role in the migration, proliferation, and differentiation of neural crest cells (2,8). These cells migrate from the neural tube to the specific regions in the embryo, where they give rise to many different types of cells including the neurons and glia of the enteric ganglia, melanocytes, facial cartilage and bone, and chromaffin cells of the adrenal medulla (7). Mutations in the EDNRB gene caused Waardenburg-Shah Syndrome 4 (3), which is characterized by changes in skin, hair, and eye coloring, hearing loss, and the Hirschsprung disease that causes severe constipation or intestinal blockage. We established the AGH-Ednrb sl/sl rat harboring null allele of the Ednrb gene (5). Homozygous mutant rats showed hearing loss with pigmentation disturbance in addition to Hirschsprung disease, which is an authentic model of Waardenburg-Shah Syndrome 4. The Ednrb null mice show abnormal splenic microarchitecture with lymphopenia, and relative reduction of B cells compared to T cells (4). To test whether similar phenotypes are produced in three rat strains bearing null mutation of Ednrb, we examined the abnormality in the thymus and spleen. Ge-

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Genetic Background Strongly Modifies the Severity of Symptoms of Hirschsprung Disease, but Not Hearing Loss in Rats Carrying Ednrbsl Mutations

Cited by 37 publications

References 50 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

White paper on guidelines concerning enteric nervous system stem cell therapy for enteric neuropathies

Lymphopenia in Ednrb-deficient rat was strongly modified by genetic background

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