Expression and Significance of Neuroligins in Myenteric Cells of Cajal in Hirschsprung's Disease

Wang, Jian; Mou, Yaru; Zhang, Qiangye; Zhang, Fan; Yang, Hongchao; Zhang, Wentong; Li, Aiwu

doi:10.1371/journal.pone.0067205

Cited by 9 publications

(6 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…To clarify potential mechanisms underlying GI dysfunction in neuroligin‐3 linked autism, we characterized expression of neuroligins and their binding partners, the neurexins, in the mouse GI tract. Neuroligins and neurexins are expressed in the rodent [Leembruggen et al, ; Wang et al, ] and human [Wang et al, ; Yang et al, ; Zhang et al, ] GI tract; however, little is known about the functional contribution of neuroligin‐3 expression in the GI tract. Nlgn1 , Nlgn2 , Nlgn3 , Nrxn1 , and Nrxn2 mRNAs are predominantly expressed in myenteric plexus‐enriched preparations of both duodenum and colon (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…These mutations include genes encoding neuroligins, a group of four postsynaptic adhesion molecules (neuroligins‐1 to 4) and their extracellular and intracellular binding partners, neurexins and SHANK3 [Sudhof, ]. Expression of genes encoding several of these proteins is reported in the GI tract [Wang et al, , ; Yang et al, ; Zhang et al, ]; however a systematic analysis of expression in both the small and large intestine and, of particular interest, in neuronal enriched samples is needed.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3

et al. 2019

View full text Add to dashboard Cite

Gastrointestinal (GI) problems constitute an important comorbidity in many patients with autism. Multiple mutations in the neuroligin family of synaptic adhesion molecules are implicated in autism, however whether they are expressed and impact GI function via changes in the enteric nervous system is unknown. We report the GI symptoms of two brothers with autism and an R451C mutation in Nlgn3 encoding the synaptic adhesion protein, neuroligin‐3. We confirm the presence of an array of synaptic genes in the murine GI tract and investigate the impact of impaired synaptic protein expression in mice carrying the human neuroligin‐3 R451C missense mutation (NL3 R451C ). Assessing in vivo gut dysfunction, we report faster small intestinal transit in NL3 R451C compared to wild‐type mice. Using an ex vivo colonic motility assay, we show increased sensitivity to GABA A receptor modulation in NL3 R451C mice, a well‐established Central Nervous System (CNS) feature associated with this mutation. We further show increased numbers of small intestine myenteric neurons in NL3 R451C mice. Although we observed altered sensitivity to GABA A receptor modulators in the colon, there was no change in colonic neuronal numbers including the number of GABA‐immunoreactive myenteric neurons. We further identified altered fecal microbial communities in NL3 R451C mice. These results suggest that the R451C mutation affects small intestinal and colonic function and alter neuronal numbers in the small intestine as well as impact fecal microbes. Our findings identify a novel GI phenotype associated with the R451C mutation and highlight NL3 R451C mice as a useful preclinical model of GI dysfunction in autism. Autism Res 2019, 12: 1043–1056 . © 2019 International Society for Autism Research, Wiley Periodicals, Inc. Lay Summary People with autism commonly experience gastrointestinal problems, however the cause is unknown. We report gut symptoms in patients with the autism‐associated R451C mutation encoding the neuroligin‐3 protein. We show that many of the genes implicated in autism are expressed in mouse gut. The neuroligin‐3 R451C mutation alters the enteric nervous system, causes gastrointestinal dysfunction, and disrupts gut microbe populations in mice. Gut dysfunction in autism could be due to mutations that affect neuronal communication.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3

et al. 2019

View full text Add to dashboard Cite

show abstract

“…In the present patient, it was not possible to compare the histological sample with those of healthy children, a scarcely available material 20. Appropriate tissue samples, correct handling, and expertise in anatomopathological interpretation are crucial to increase the accuracy of diagnosis of low ICC count.…”

Section: Discussionmentioning

confidence: 85%

Doença de Hirschsprung – Dismotilidade intestinal pós‐cirúrgica

Romaneli

Ribeiro

Bustorff‐Silva

et al. 2016

Revista Paulista de Pediatria

View full text Add to dashboard Cite

Hirschsprung's disease presenting as total colonic aganglionosis has clinical and surgical characteristics that differentiate it from the classic forms, complicating the diagnosis and the clinical and surgical management. The postoperative course may be associated with permanent morbidity due to intestinal dysmotility. The numerical reduction or alteration of neural connections in the interstitial cells of Cajal may represent a possible physiopathological basis for the condition.

show abstract

“…Neuroligin proteins are present in enteric neurons [28][29][30] . As the enteric nervous system plays a major role in regulating gastrointestinal function, we postulated that the R451C mutation would affect motility.…”

Section: Representative Resultsmentioning

confidence: 99%

Video Imaging and Spatiotemporal Maps to Analyze Gastrointestinal Motility in Mice

Swaminathan

Hill‐Yardin

Ellis

et al. 2016

JoVE

View full text Add to dashboard Cite

The enteric nervous system (ENS) plays an important role in regulating gastrointestinal (GI) motility and can function independently of the central nervous system. Changes in ENS function are a major cause of GI symptoms and disease and may contribute to GI symptoms reported in neuropsychiatric disorders including autism. It is well established that isolated colon segments generate spontaneous, rhythmic contractions known as Colonic Migrating Motor Complexes (CMMCs). A procedure to analyze the enteric neural regulation of CMMCs in ex vivo preparations of mouse colon is described. The colon is dissected from the animal and flushed to remove fecal content prior to being cannulated in an organ bath. Data is acquired via a video camera positioned above the organ bath and converted to high-resolution spatiotemporal maps via an inhouse software package. Using this technique, baseline contractile patterns and pharmacological effects on ENS function in colon segments can be compared over 3-4 hr. In addition, propagation length and speed of CMMCs can be recorded as well as changes in gut diameter and contraction frequency. This technique is useful for characterizing gastrointestinal motility patterns in transgenic mouse models (and in other species including rat and guinea pig). In this way, pharmacologically induced changes in CMMCs are recorded in wild type mice and in the Neuroligin-3 R451C mouse model of autism. Furthermore, this technique can be applied to other regions of the GI tract including the duodenum, jejunum and ileum and at different developmental ages in mice. Video LinkThe video component of this article can be found at

show abstract

Expression and Significance of Neuroligins in Myenteric Cells of Cajal in Hirschsprung's Disease

Cited by 9 publications

References 31 publications

Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3

Gastrointestinal dysfunction in patients and mice expressing the autism‐associated R451C mutation in neuroligin‐3

Doença de Hirschsprung – Dismotilidade intestinal pós‐cirúrgica

Video Imaging and Spatiotemporal Maps to Analyze Gastrointestinal Motility in Mice

Contact Info

Product

Resources

About