Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism

David M. James, Robert Kozol, Yuji Kajiwara, Adam L. Wahl, Emily C. Storrs, Joseph D. Buxbaum, Mason Klein, Baharak Moshiree, Julia E. Dallman

Research output: Contribution to journalArticle

4 Scopus citations


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.

Original languageEnglish (US)
Article number3
JournalMolecular Autism
Issue number1
StatePublished - Jan 31 2019


  • Digestive transit
  • Enteroendocrine
  • Peristaltic rate
  • Phelan-McDermid syndrome

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Neuroscience
  • Developmental Biology
  • Psychiatry and Mental health

Fingerprint Dive into the research topics of 'Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism'. Together they form a unique fingerprint.

  • Cite this

    James, D. M., Kozol, R., Kajiwara, Y., Wahl, A. L., Storrs, E. C., Buxbaum, J. D., Klein, M., Moshiree, B., & Dallman, J. E. (2019). Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism. Molecular Autism, 10(1), [3].