scholarly journals RET overactivation leads to concurrent Hirschsprung disease and intestinal ganglioneuromas

Development ◽  
2020 ◽  
Vol 147 (21) ◽  
pp. dev190900
Author(s):  
Nandor Nagy ◽  
Richard A. Guyer ◽  
Ryo Hotta ◽  
Dongcheng Zhang ◽  
Donald F. Newgreen ◽  
...  
Keyword(s):  
Neural Crest Cell ◽  
Hirschsprung Disease ◽  
Neuronal Progenitors ◽  
Proliferation And Differentiation ◽  
Cellular Context ◽  
Neural Crest Cell Migration ◽  
Concurrent Development ◽  
Crest Cell ◽  
Associated Tumors ◽  
Intestinal Aganglionosis

ABSTRACTAppropriately balanced RET signaling is of crucial importance during embryonic neural crest cell migration, proliferation and differentiation. RET deficiency, for example, leads to intestinal aganglionosis (Hirschsprung disease), whereas overactive RET can lead to multiple endocrine neoplasia (MEN) syndromes. Some RET mutations are associated with both intestinal aganglionosis and MEN-associated tumors. This seemingly paradoxical occurrence has led to speculation of a ‘Janus mutation’ in RET that causes overactivation or impairment of RET activity depending on the cellular context. Using an intestinal catenary culture system to test the effects of GDNF-mediated RET activation, we demonstrate the concurrent development of distal colonic aganglionosis and intestinal ganglioneuromas. Interestingly, the tumors induced by GDNF stimulation contain enteric neuronal progenitors capable of reconstituting an enteric nervous system when transplanted into a normal developmental environment. These results suggest that a Janus mutation may not be required to explain co-existing Hirschsprung disease and MEN-associated tumors, but rather that RET overstimulation alone is enough to cause both phenotypes. The results also suggest that reprogramming tumor cells toward non-pathological fates may represent a possible therapeutic avenue for MEN-associated neoplasms.

scholarly journals Skip segment Hirschsprung disease: modelling the trans-mesenteric origin of the enteric nervous system in the human colon

2019 ◽  
Author(s):  
Donald F Newgreen ◽  
James M Osborne ◽  
Dongcheng Zhang
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Growth Parameters ◽  
Neural Crest Cell ◽  
Hirschsprung Disease ◽  
Division Rate ◽  
Intestinal Growth ◽  
Developmental Anatomy ◽  
Neural Crest Cell Migration ◽  
Crest Cell

ABSTRACTSkip segment Hirschsprung disease is a difficult to explain human enteric neuropathy where a ganglionated region lies within a region of total colonic aganglionosis.. Recently, trans-mesenteric migration was described in the mouse intestine whereby neural crest cells migrate via the mesentery across a U-shape gut loop from the midgut to the hindgut: this could explain skip segment Hirschsprung disease. To investigate this, human intestinal growth parameters were derived from published sources and correlated with enteric neural crest cell migration. These processes were then simulated using agent based mathematical models scaled to human intestinal growth. A Hirschsprung-associated slowing of migration was imposed and trans-mesenteric migration was allowed. From the developmental anatomy we conclude that trans-mesenteric migration is unlikely in normal human embryogenesis, but with a Hirschsprung-associated slowing of enteric neural crest cell migration it could occur at Carnegie stages 17 and 18. By varying the division rate of enteric neural crest agents we could reproduce full colonisation, short segment, long segment and skip segment Hirschsprung and hypoganglionic segments.Summary StatementSkip segment Hirschsprung disease in humans challenges current explanations. Mathematical modelling shows how this birth defect could develop.

Early Death of Neural Crest Cells is Responsible for Total Enteric Aganglionosis in Sox10Dom/Sox10Dom Mouse Embryos

1999 ◽  
Vol 2 (6) ◽  
pp. 559-569 ◽  
Author(s):  
Raj P. Kapur
Keyword(s):  
Neural Crest ◽  
Neural Crest Cell ◽  
Hirschsprung Disease ◽  
Early Death ◽  
Neural Crest Cells ◽  
Wild Type ◽  
Crest Cell ◽  
Insight Into ◽  
Intestinal Aganglionosis ◽  
Migratory Pathway

Intestinal aganglionosis results from homologous genetic defects in humans and mice, including mutations of Sox10, which encodes a transcription factor expressed in neural crest cells. To gain insight into the embryological basis for this condition, the phenotype and pathogenesis of intestinal aganglionosis in Sox10 Dom/ Sox10 Dom embryos were studied. The distribution of enteric neural precursors and other neural crest derivatives in Sox10 Dom/ Sox10 Dom embryos was analyzed with immunochemical and transgenic markers. The ability of wild-type neural crest cells to colonize Sox10 Dom/ Sox10 Dom intestinal ex-plants was evaluated by appositional grafts under the renal capsule. Apoptosis was studied by TUNEL labeling. Sox10 Dom/ Sox10 Dom embryos died pre- or perinatally with total enteric aganglionosis and hypoplasia or agenesis of nonenteric ganglia. Mutant crest cells failed to colonize any portion of the Sox10 Dom/ Sox10 Dom gut, but wild-type neural crest cells were able to colonize explanted segments of Sox10 Dom/ Sox10 Dom embryonic intestine. In Sox10 Dom/ Sox10 Dom embryos, apoptosis was increased in sites of early neural crest cell development, before these cells enter the gut. Sox10 Dom/ Sox10 Dom embryos are one of many genetic animal models for human Hirschsprung disease. The underlying problem is probably not the enteric microenvironment, since Sox10 Dom/ Sox10 Dom intestine supports colonization and neuronal differentiation by wild-type neural crest cells. Instead, excessive cell death occurs in mutant neural crest cells early in their migratory pathway. Comparison with other models suggests that genetic heterogeneity of aganglionosis correlates with different pathogenetic mechanisms.

scholarly journals Association between miR-492 rs2289030 G>C and susceptibility to Hirschsprung disease in southern Chinese children

2020 ◽  
Vol 48 (10) ◽  
pp. 030006052096168
Author(s):  
Yi Zheng ◽  
Yanqing Liu ◽  
Mi Wang ◽  
Qiuming He ◽  
Xiaoli Xie ◽  
...  
Keyword(s):  
Ganglion Cells ◽  
Quantitative Polymerase Chain Reaction ◽  
Multivariate Logistic Regression Analysis ◽  
Neural Crest Cell ◽  
Hirschsprung Disease ◽  
Chinese Children ◽  
Southern Chinese ◽  
Neural Crest Cell Migration ◽  
Differentiation And Proliferation ◽  
Crest Cell

Objective Hirschsprung disease (HSCR) originates from disruption of normal neural crest cell migration, differentiation, and proliferation during the fifth to eighth weeks of gestation. This results in the absence of intestinal ganglion cells in the distal intestinal tract. However, genetic variations affecting embryonic development of intestinal ganglion cells are unclear. Therefore, this study aimed to investigated the potential value of miR-492 rs2289030 G>C as a marker of susceptibility to HSCR Methods In this case–control study in southern Chinese children, we collected samples from 1473 controls and 1470 patients with HSCR. TaqMan genotyping of miR-492 rs2289030 G>C was performed by real-time fluorescent quantitative polymerase chain reaction. Results Multivariate logistic regression analysis showed that there was no significant association between the presence of the miR-492 rs2289030 G>C polymorphism and susceptibility to HSCR by evaluating the values of pooled odds ratios and 95% confidence intervals. Similarly, among different HSCR subtypes, rs2289030 G>C was also not associated with HSCR in hierarchical analysis. Conclusions Our results suggest that the miR-492 rs2289030 G>C polymorphism is not associated with susceptibility to HSCR in southern Chinese children. These results need to be further confirmed by investigating a more diverse ethnic population of patients with HSCR.

scholarly journals Proliferation dynamics associated with cranial neural crest cell migration

2011 ◽  
Vol 356 (1) ◽  
pp. 197
Author(s):  
Dennis A. Ridenour ◽  
Rebecca McLennan ◽  
Jessica M. Teddy ◽  
Katherine W. Prather ◽  
Craig L. Semerad ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Neural Crest Cell ◽  
Cranial Neural Crest ◽  
Cranial Neural Crest Cell ◽  
Neural Crest Cell Migration ◽  
Crest Cell

scholarly journals Timing of odontogenic neural crest cell migration and tooth-forming capability in mice

2003 ◽  
Vol 226 (4) ◽  
pp. 713-718 ◽  
Author(s):  
Yanding Zhang ◽  
Shusheng Wang ◽  
Yiqiang Song ◽  
Jun Han ◽  
Yang Chai ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Neural Crest Cell ◽  
Neural Crest Cell Migration ◽  
Crest Cell

scholarly journals Role of FGF signalling in neural crest cell migration during early chick embryo development

Zygote ◽  
2018 ◽  
Vol 26 (6) ◽  
pp. 457-464 ◽  
Author(s):  
Xiao-tan Zhang ◽  
Guang Wang ◽  
Yan Li ◽  
Manli Chuai ◽  
Kenneth Ka Ho Lee ◽  
...  
Keyword(s):  
Neural Crest ◽  
Neural Tube ◽  
Neural Crest Cell ◽  
Dominant Negative ◽  
Neural Tubes ◽  
Dorsal Neural Tube ◽  
Neural Crest Cell Migration ◽  
Fgf Signalling ◽  
Crest Cell

SummaryFibroblast growth factor (FGF) signalling acts as one of modulators that control neural crest cell (NCC) migration, but how this is achieved is still unclear. In this study, we investigated the effects of FGF signalling on NCC migration by blocking this process. Constructs that were capable of inducing Sprouty2 (Spry2) or dominant-negative FGFR1 (Dn-FGFR1) expression were transfected into the cells making up the neural tubes. Our results revealed that blocking FGF signalling at stage HH10 (neurulation stage) could enhance NCC migration at both the cranial and trunk levels in the developing embryos. It was established that FGF-mediated NCC migration was not due to altering the expression of N-cadherin in the neural tube. Instead, we determined that cyclin D1 was overexpressed in the cranial and trunk levels when Sprouty2 was upregulated in the dorsal neural tube. These results imply that the cell cycle was a target of FGF signalling through which it regulates NCC migration at the neurulation stage.

scholarly journals Foxc2 is required for proper cardiac neural crest cell migration, outflow tract septation, and ventricle expansion

2018 ◽  
Vol 247 (12) ◽  
pp. 1286-1296 ◽  
Author(s):  
Kimberly E. Inman ◽  
Carlo Donato Caiaffa ◽  
Kristin R. Melton ◽  
Lisa L. Sandell ◽  
Annita Achilleos ◽  
...  
Keyword(s):  
Cell Migration ◽  
Neural Crest ◽  
Neural Crest Cell ◽  
Outflow Tract ◽  
Cardiac Neural Crest ◽  
Neural Crest Cell Migration ◽  
Crest Cell
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