論文 - 詳細
RRC ID | 59942 |
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著者 | James DM, Kozol RA, Kajiwara Y, Wahl AL, Storrs EC, Buxbaum JD, Klein M, Moshiree B, Dallman JE. |
タイトル | Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism. |
ジャーナル | Mol Autism |
Abstract |
Background and aims:Autism spectrum disorder (ASD) is currently estimated to affect more than 1% of the world population. For people with ASD, gastrointestinal (GI) distress is a commonly reported but a poorly understood co-occurring symptom. Here, we investigate the physiological basis for GI distress in ASD by studying gut function in a zebrafish model of Phelan-McDermid syndrome (PMS), a condition caused by mutations in the SHANK3 gene. Methods:To generate a zebrafish model of PMS, we used CRISPR/Cas9 to introduce clinically related C-terminal frameshift mutations in shank3a and shank3b zebrafish paralogues (shank3abΔC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abΔC+/- heterozygotes. Human SHANK3 mRNA was then used to rescue DT phenotypes in larval zebrafish. Results:Significantly slower rates of DT peristaltic contractions (p < 0.001) with correspondingly prolonged passage time (p < 0.004) occurred in shank3abΔC+/- mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abΔC+/- mutants produced larvae with intestinal bulb emptying similar to wild type (WT), but still deficits in posterior intestinal motility. Serotonin-positive enteroendocrine cells (EECs) were significantly reduced in both shank3abΔC+/- and shank3abΔC-/- mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abΔC+/- larvae. Conclusions:Our data and rescue experiments support mutations in SHANK3 as causal for GI transit and motility abnormalities. Reductions in serotonin-positive EECs and serotonin-filled ENS boutons suggest an endocrine/neural component to this dysmotility. This is the first study to date demonstrating DT dysmotility in a zebrafish single gene mutant model of ASD. |
巻・号 | 10 |
ページ | 3 |
公開日 | 2019-1-1 |
DOI | 10.1186/s13229-018-0250-4 |
PII | 250 |
PMID | 30733854 |
PMC | PMC6357389 |
MeSH | Animals Autistic Disorder / genetics* Autistic Disorder / physiopathology Enteric Nervous System / cytology Enteric Nervous System / metabolism Enteroendocrine Cells / metabolism Gastrointestinal Motility* Intestinal Mucosa / metabolism Intestines / cytology Intestines / growth & development Intestines / physiology Mutation Nerve Tissue Proteins / genetics* Neurons / metabolism Protein Isoforms / genetics Protein Isoforms / metabolism Serotonin / metabolism Zebrafish Zebrafish Proteins / genetics* |
IF | 5.869 |
引用数 | 4 |
リソース情報 | |
ゼブラフィッシュ | Tg(vglut2a:loxP-DsRed-loxP-GFP) |