RRC ID 59942
Author James DM, Kozol RA, Kajiwara Y, Wahl AL, Storrs EC, Buxbaum JD, Klein M, Moshiree B, Dallman JE.
Title Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism.
Journal 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.
Volume 10
Pages 3
Published 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
Times Cited 4
Zebrafish Tg(vglut2a:loxP-DsRed-loxP-GFP)