Sonic Hedgehog Signaling and VACTERL Association

Ngan, Elly Sau-Wai; Kim, Kyoung-Han; Hui, Chi‐chung

doi:10.1159/000345725

Cited by 30 publications

(30 citation statements)

References 188 publications

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“…a nodular expression pattern in glomeruli). These data suggested that HHIP might delay or disorient the usual gradient SHH expression pattern establishment from distal (high) to proximal (low) [25,26], since HHIP is expressed in cells adjacent to those expressing SHH to antagonise its activity [12]. Our in vitro studies in MK4 and UB tip cells with or without high-glucose media elucidated a potential counterbalance between Hhip and Shh gene expression in both differentiated UB and MM epithelium, and hint that this interaction is critical in the nephrogenic process.…”

Section: Discussionmentioning

confidence: 92%

“…During normal kidney development, the balance of HHIP-SHH signalling appears to be critical in the control of a series of sequential events of nephrogenic processes [25,26]. Upon high glucose insult, for example, in our murine model, the offspring of diabetic dams had a markedly different expression pattern of HHIP when compared with offspring of normal non-diabetic dams.…”

Section: Discussionmentioning

confidence: 98%

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Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP)

et al. 2014

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Aims/hypothesis We hypothesised that maternal diabetes impairs kidney formation in offspring via augmented expression of hedgehog interacting protein (HHIP). Our gene-array results were performed in neonatal kidneys from our murine model of maternal diabetes and indicated that Hhip expression was significantly modulated by maternal diabetes. Methods We systematically examined the functional role of HHIP in kidney formation in our murine maternal diabetes model and elucidated the potential mechanisms related to dysnephrogenesis in vitro. Results The kidneys of the offspring of diabetic dams, compared with those of the offspring of control non-diabetic dams, showed retardation of development-small kidneys and less ureteric bud (UB) branching morphogenesis. Augmented HHIP expression was observed in the offspring of diabetic dams, initially localised to differentiated metanephric mesenchyme and UB epithelium and subsequently in maturing glomerular endothelial and tubulointerstitial cells. The heightened HHIP targeting TGF-β1 signalling was associated with dysmorphogenesis. In vitro, HHIP overexpression decreased sonic hedgehog and paired box gene 2 proteins (SHH and PAX2, respectively) and increased transcriptional nuclear factor-kappa B (NFκB, p50/p65), phosphorylation of p53, and TGF-β1 expression. In contrast, overexpression of PAX2 inhibited HHIP and NFκB and activated SHH, N-myc and p27Kip1 expression. Moreover, high glucose stimulated HHIP expression, and then targeted TGF-β1 signalling. Thus, PAX2, via a negative autocrine feedback mechanism, attenuated the stimulatory effect of high glucose on HHIP expression. Conclusions/interpretation Maternal diabetes modulates kidney formation in young progeny mediated, at least in part, via augmented HHIP expression.

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Section: Discussionmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 98%

Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP)

et al. 2014

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“…Reports of true familial cases of VACTERL association (≥3 component features; CFs) are rare; however, the prevalence of single CFs in relatives of patients with VACTERL association is ~10% suggesting a genetic etiology to some extent [37, 39]. The deletion of genes in the Sonic hedgehog pathway (for example SHH , GLI , and HOXD13 ) modeled in mice mimics many of the same malformations as found in VACTERL association, which have resulted in a profound interest in these genes [40]. However, only mutations of HOXD13 [41] and FOXF1 [42, 43] have been reported in humans with VACTERL association, while SHH and GLI2 mutations are associated with holoprosencephaly [40].…”

Section: Discussionmentioning

confidence: 99%

“…The deletion of genes in the Sonic hedgehog pathway (for example SHH , GLI , and HOXD13 ) modeled in mice mimics many of the same malformations as found in VACTERL association, which have resulted in a profound interest in these genes [40]. However, only mutations of HOXD13 [41] and FOXF1 [42, 43] have been reported in humans with VACTERL association, while SHH and GLI2 mutations are associated with holoprosencephaly [40]. Furthermore, mutations in ZIC3 have been reported in several cases of VACTERL association [43–45].…”

Section: Discussionmentioning

confidence: 99%

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

et al. 2016

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BackgroundThe vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome are rare conditions. We aimed to present two cases with the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser co-occurrence from our local surgical center and through a systematic literature search detect published cases. Furthermore, we aimed to collect existing knowledge in the embryopathogenesis and genetics in order to discuss a possible link between the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome.Case presentationOur first case was a white girl delivered by caesarean section at 37 weeks of gestation; our second case was a white girl born at a gestational age of 40 weeks. A co-occurrence of vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome was diagnosed in both cases.We performed a systematic literature search in PubMed ((VACTERL) OR (VATER)) AND ((MRKH) OR (Mayer-Rokitansky-Küster-Hauser) OR (mullerian agenesis) OR (mullerian aplasia) OR (MURCS)) without limitations. A similar search was performed in Embase and the Cochrane library. We added two cases from our local center.All cases (n = 9) presented with anal atresia and renal defect. Vertebral defects were present in eight patients. Rectovestibular fistula was confirmed in seven patients. Along with the uterovaginal agenesis, fallopian tube aplasia appeared in five of nine cases and in two cases ovarian involvement also existed.ConclusionsThe co-occurrence of the vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association and Mayer-Rokitansky-Küster-Hauser syndrome is extremely rare. This group of patients has unusual phenotypic characteristics. The long-term outcome after treatment of defects is not well reported. A single unifying cause is not known and the etiology probably includes both genetic and non-genetic causes. We stress the importance of future studies to optimized treatment, follow-up, and etiology.

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“…Suppressor of Fused (Sufu) is a key negative regulator of Gli transcription factors, it reduces Gli transcriptional activity by promoting the formation of Gli3 repressor (Gli3 R ) and the cytoplasmic sequestration of Gli activators (Gli A ) 18,19 .…”

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confidence: 99%

Identification of GLI Mutations in Patients With Hirschsprung Disease That Disrupt Enteric Nervous System Development in Mice

et al. 2015

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Sonic Hedgehog Signaling and VACTERL Association

Cited by 30 publications

References 188 publications

Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP)

Maternal diabetes modulates kidney formation in murine progeny: the role of hedgehog interacting protein (HHIP)

Vertebral defect, anal atresia, cardiac defect, tracheoesophageal fistula/esophageal atresia, renal defect, and limb defect association with Mayer-Rokitansky-Küster-Hauser syndrome in co-occurrence: two case reports and a review of the literature

Identification of GLI Mutations in Patients With Hirschsprung Disease That Disrupt Enteric Nervous System Development in Mice

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