The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung's Disease

Carniti, Cristiana; Belluco, Sara; Riccardi, Elena; Cranston, Aaron; Mondellini, Piera; Ponder, Bruce A.J.; Scanziani, Eugenio; Bongarzone, Italia

doi:10.2353/ajpath.2006.050607

Cited by 34 publications

(18 citation statements)

References 36 publications

(58 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Moreover, in ret +/C620R mice that have an enteric neuronal hypoganglionic phenotype 16 reminiscent of the histopathology observed in some CIPO patients, 27,29 Apob was markedly overexpressed. APOB is a major constituent of the plasma lipoprotein, and in mammals is synthesized in two different tissues, i.e.…”

Section: Discussionmentioning

confidence: 86%

“…This latter finding is reminiscent of an enteric neuronal hypoganglionic phenotype observed in heterozygous ret C620R/+ mice 16 and shares similarities with the histopathology of some CIPO patients. 14,27,28 The similarity of the rad21 suppression phenotype in zebrafish to the neuronal defects of heterozygous ret C620R/+ mice prompted us to test whether those two genes might interact genetically. We showed that RET and RAD21 interact epistatically during differentiation or maintenance of enteric neurons.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Mutations in RAD21 Disrupt Regulation of APOB in Patients With Chronic Intestinal Pseudo-Obstruction

et al. 2015

View full text Add to dashboard Cite

Background & Aims Chronic intestinal pseudo-obstruction (CIPO) is characterized by severe intestinal dysmotility that mimicks a mechanical sub-occlusion with no evidence of gut obstruction. We searched for genetic variants associated with CIPO to increase our understanding of its pathogenesis and indentify potential biomarkers. Methods We performed whole-exome sequencing of genomic DNA from patients with familial CIPO syndrome. Blood and lymphoblastoid cells were collected from patients and controls (individuals without CIPO); levels of mRNA and proteins were analyzed by quantitative reverse transcription PCR, immunoblot, and mobility shift assays. cDNAs were transfected into HEK293 cells. Expression of rad21 was suppressed in zebrafish embryos using a splice-blocking morpholino (rad21a MO). Gut tissues were collected and analyzed. Results We identified a homozygous mutation (p.622, encodes Ala>Thr) in RAD21 in patients from a consanguineous family with CIPO. Expression of RUNX1, a target of RAD21, was reduced in cells from patients with CIPO compared with controls. In zebrafish, suppression of rad21a reduced expression of runx1; this phenotype was corrected by injection of human RAD21 mRNA, but not with the mRNA from the mutated p.622 allele. rad21a MO zebrafish had delayed intestinal transit and greatly reduced numbers of enteric neurons, similar to patients with CIPO. This defect was greater in zebrafish with suppressed expression of ret and rad21, indicating their interaction in regulation of gut neurogenesis. The promoter region of APOB bound RAD21 but not RAD21 p.622 Ala>Thr; expression of wild-type RAD21 in HEK293 cells repressed expression of APOB, compared with control vector. The gut-specific isoform of APOB (APOB48) is overexpressed in sera from patients with CIPO who carry the RAD21 mutation. APOB48 is also overexpressed in sporadic CIPO in sera and gut biopsies. Conclusions Some patients with CIPO carry mutations in RAD21 that disrupt the ability of its product to regulate genes such as RUNX1 and APOB. Reduced expression of rad21 in zebrafish, and dysregulation of these target genes, disrupts intestinal transit and development of enteric neurons.

show abstract

Section: Discussionmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Mutations in RAD21 Disrupt Regulation of APOB in Patients With Chronic Intestinal Pseudo-Obstruction

et al. 2015

View full text Add to dashboard Cite

show abstract

“…Revealing that RET is physiologically required for the survival of colonic neurons, we set out to examine the potential involvement of Ret-dependent cell survival in ENS pathology, HSCR in particular. Although several Ret mutants have previously been reported to display aganglionosis (11,(18)(19)(20)(21)(22)(23) and so resemble HSCR to some extent, several significant differences do exist in the phenotype of those animals and that of HSCR patients. For instance, in those Ret mutant mice, the aganglionic phenotype exhibits full penetrance and is associated with kidney deficits.…”

Section: Physiological Requirement Of Ret For the Survival Of Entericmentioning

confidence: 99%

Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice

Uesaka¹,

Nagashimada²,

Yonemura³

et al. 2008

J. Clin. Invest.

157

172

View full text Add to dashboard Cite

Mutations in the RET gene are the primary cause of Hirschsprung disease (HSCR), or congenital intestinal aganglionosis. However, how RET malfunction leads to HSCR is not known. It has recently been shown that glial cell line-derived neurotrophic factor (GDNF) family receptor α1 (GFRα1), which binds to GDNF and activates RET, is essential for the survival of enteric neurons. In this study, we investigated Ret regulation of enteric neuron survival and its potential involvement in HSCR. Conditional ablation of Ret in postmigratory enteric neurons caused widespread neuronal death in the colon, which led to colonic aganglionosis. To further examine this finding, we generated a mouse model for HSCR by reducing Ret expression levels. These mice recapitulated the genetic and phenotypic features of HSCR and developed colonic aganglionosis due to impaired migration and successive death of enteric neural crest-derived cells. Death of enteric neurons was also induced in the colon, where reduction of Ret expression was induced after the period of enteric neural crest cell migration, indicating that diminished Ret expression directly affected the survival of colonic neurons. Thus, enteric neuron survival is sensitive to RET dosage, and cell death is potentially involved in the etiology of HSCR.

show abstract

“…RET signaling also maintains the enteric nervous system, and loss of RET function in these neurons leads to Hirschsprung’s disease, a condition characterized by absence of enteric ganglia [99]. Importantly, this role of RET is reproduced in both RET knockout [100] and RET knockin mice with RET C620R mutations (mixed Hirschsprung’s/MTC phenotype)[101,102]. Finally it is important to remember that GDNF/RET signaling has a clearly established role in driving spermatogonial stem cell self-renewal in the testis, and is therefore essential to male fertility [103–106].…”

Section: Molecular Pathway Dysregulations In Human C-cell Oncogenimentioning

confidence: 99%

Thyroid C-Cell Biology and Oncogenic Transformation

Cote

Grubbs

Hofmann

2015

Recent Results in Cancer Research

View full text Add to dashboard Cite

The thyroid parafollicular cell, or commonly named “C-cell,” functions in serum calcium homeostasis. Elevations in serum calcium trigger release of calcitonin from the C-cell, which in turn functions to inhibit absorption of calcium by the intestine, resorption of bone by the osteoclast, and reabsorption of calcium by renal tubular cells. Oncogenic transformation of the thyroid C-cell is thought to progress through a hyperplastic process prior to malignancy with increasing levels of serum calcitonin serving as a biomarker for tumor burden. The discovery that Multiple Endocrine Neoplasia, type 2 is caused by activating mutations of the RET gene serves to highlight the RET-RAS-MAPK signaling pathway in both initiation and progression of medullary thyroid carcinoma. Thyroid C-cells are known to express RET at high levels relative to most cell types, therefore aberrant activation of this receptor is targeted primarily to the C-cell, providing one possible cause of tissue-specific oncogenesis. The role of RET signaling in normal C-cell function is unknown though calcitonin gene transcription appears to be sensitive to RET activation. Beyond RET the modeling of oncogenesis in animals and screening of human tumors for candidate gene mutations has uncovered mutation of RAS family members and inactivation of Rb1 regulatory pathway as potential mediators of C-cell transformation. A growing understanding of how RET interacts with these pathways, both in normal C-cell function and during oncogenic transformation will help in the development of novel molecular targeted therapies.

show abstract

The RetC620R Mutation Affects Renal and Enteric Development in a Mouse Model of Hirschsprung's Disease

Cited by 34 publications

References 36 publications

Mutations in RAD21 Disrupt Regulation of APOB in Patients With Chronic Intestinal Pseudo-Obstruction

Mutations in RAD21 Disrupt Regulation of APOB in Patients With Chronic Intestinal Pseudo-Obstruction

Diminished Ret expression compromises neuronal survival in the colon and causes intestinal aganglionosis in mice

Thyroid C-Cell Biology and Oncogenic Transformation

Contact Info

Product

Resources

About