Pan-enteric neuropathy and dysmotility are present in a mouse model of short-segment Hirschsprung disease and may contribute to post-pullthrough morbidity

Bhave, Sukhada; Arciero, Emily; Baker, Corey; Ho, Wing Lam N.; Guyer, Richard A.; Hotta, Ryo; Goldstein, Allan M.

doi:10.1016/j.jpedsurg.2020.04.002

Cited by 9 publications

(11 citation statements)

References 25 publications

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“…Similar observations of diffuse abnormal function throughout the GI tract have been made in mouse models of HSCR. For example, increased gastric emptying has been described in Ednrb −/− and Sox10 Dom/+ mouse-models of HSCR ( Musser et al, 2015 ; Bhave et al, 2021 ). Complete loss of colonic migrating motor complexes has been observed in the proximal ganglionic colon of Ednrb −/− , Et-3 −/− , and Gdnrf +/- HSCR mice ( Ro et al, 2006 ; Roberts et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, an overabundance of nitrergic innervation and a deficit of cholinergic innervation has been reported in the proximal colon of HSCR patient samples and mice with HSCR ( Zaitoun et al, 2013 ; Cheng et al, 2016 ). Furthermore, several animal models of HSCR, including Ednrb −/− , Et-3 −/− , and Gdnrf +/- mice, which are characterized by variable lengths of aganglionic rectum and distal colon ( Ro et al, 2006 ; Barnes and Spencer, 2015 ), exhibit a hypoganglionic phenotype in the colon proximal to the aganglionic segment characterized by decreased myenteric neuronal density ( Roberts et al, 2008 ; Bhave et al, 2021 ). These changes in the proximal colon are associated with altered motility ( Ro et al, 2006 ).…”

Section: Introductionmentioning

confidence: 99%

“…We recently demonstrated that these structural ENS abnormalities in HSCR extend proximally to the small intestine and stomach. Ednrb −/− mice showed reduced density of myenteric ganglia and neuronal fibers in the small intestine while the myenteric neuronal packing density was increased in the stomach ( Bhave et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

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Ednrb−/− mice with hirschsprung disease are missing Gad2-expressing enteric neurons in the ganglionated small intestine

Bhave

Guyer

Picard

et al. 2022

Front. Cell Dev. Biol.

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Hirschsprung disease is most often characterized by aganglionosis limited to the distal colon and rectum, and mice lacking the Endothelin receptor type B (Ednrb) faithfully recapitulate this phenotype. However, despite the presence of enteric ganglia in the small intestine, both human patients and Ednrb−/− mice suffer from dysmotility and altered gastrointestinal function, thus raising the possibility of enteric nervous system (ENS) abnormalities proximal to the aganglionic region. We undertook the present study to determine whether abnormalities with the ENS in ganglionated regions may account for abnormal gastrointestinal function. We performed single-cell RNA sequencing on ENS cells from the small intestine of Ednrb−/− mice and compared the results to a published single-cell dataset. Our results identified a missing population of neurons marked by the enzyme Gad2, which catalyzes the production of γ-Aminobutyric acid (GABA), in the small intestine of Ednrb−/− animals. This result was confirmed by immunostaining enteric ganglia from Ednrb−/− mice and their wild-type littermates. These data show for the first time that ganglionated regions of the Hirschsprung gut lack a neuronal subpopulation, which may explain the persistent gastrointestinal dysfunction after surgical correction of Hirschsprung disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Ednrb−/− mice with hirschsprung disease are missing Gad2-expressing enteric neurons in the ganglionated small intestine

Bhave

Guyer

Picard

et al. 2022

Front. Cell Dev. Biol.

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“…The length of the small intestine travelled by the carmine red dye was measured as a proportion of the total length of the small intestine. Small intestinal transit was calculated as the percent of small intestine travelled by the carmine red dye 21 …”

Section: Methodsmentioning

confidence: 99%

“…Images were analyzed using the Image J software. Hu+ neuronal cell bodies and Tuj1+ neuronal fiber density were quantified per high‐power field from three images per animal 21 …”

Section: Methodsmentioning

confidence: 99%

Tamoxifen administration alters gastrointestinal motility in mice

Bhave

Cheng

et al. 2022

Neurogastroenterology Motil

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Background Tamoxifen is widely used for Cre‐estrogen receptor‐mediated genomic recombination in transgenic mouse models to mark cells for lineage tracing and to study gene function. However, recent studies have highlighted off‐target effects of tamoxifen in various tissues and cell types when used for induction of Cre recombination. Despite the widespread use of these transgenic Cre models to assess gastrointestinal (GI) function, the effect of tamoxifen exposure on GI motility has not been described. Methods We examined the effects of tamoxifen on GI motility by measuring total GI transit, gastric emptying, small intestinal transit, and colonic contractility in wild‐type adult mice. Key Results We observed a significant delay in total GI transit in tamoxifen‐treated mice, with unaltered gastric emptying, accelerated small intestinal transit, and abnormal colonic motility. Conclusion Our findings highlight the importance of considering GI motility alterations induced by tamoxifen when designing protocols that utilize tamoxifen as a Cre‐driver for studying GI function.

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Reducing Underdiagnosis of Hirschsprung-Associated Enterocolitis: A Novel Scoring System

Lewit

Veras

Cowles

et al. 2021

Journal of Surgical Research

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Pan-enteric neuropathy and dysmotility are present in a mouse model of short-segment Hirschsprung disease and may contribute to post-pullthrough morbidity

Cited by 9 publications

References 25 publications

Ednrb−/− mice with hirschsprung disease are missing Gad2-expressing enteric neurons in the ganglionated small intestine

Ednrb−/− mice with hirschsprung disease are missing Gad2-expressing enteric neurons in the ganglionated small intestine

Tamoxifen administration alters gastrointestinal motility in mice

Reducing Underdiagnosis of Hirschsprung-Associated Enterocolitis: A Novel Scoring System

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