[article]
| Titre : |
Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism |
| Type de document : |
Texte imprimé et/ou numérique |
| Auteurs : |
D. M. JAMES, Auteur ; R. A. KOZOL, Auteur ; Y. KAJIWARA, Auteur ; A. L. WAHL, Auteur ; E. C. STORRS, Auteur ; Joseph D. BUXBAUM, Auteur ; M. KLEIN, Auteur ; B. MOSHIREE, Auteur ; J. E. DALLMAN, Auteur |
| Article en page(s) : |
3 p. |
| Langues : |
Anglais (eng) |
| Mots-clés : |
*Digestive transit *Enteroendocrine *Peristaltic rate *Phelan-McDermid syndrome approved by the Institutional Animal Care and Use Committee of University of Miami.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
| Index. décimale : |
PER Périodiques |
| Résumé : |
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 (shank3abDeltaC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abDeltaC (+/-) 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 shank3abDeltaC (+/-) mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abDeltaC (+/-) 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 shank3abDeltaC (+/-) and shank3abDeltaC (-/-) mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abDeltaC (+/-) 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. |
| En ligne : |
https://dx.doi.org/10.1186/s13229-018-0250-4 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 |
in Molecular Autism > 10 (2019) . - 3 p.
[article] Intestinal dysmotility in a zebrafish (Danio rerio) shank3a;shank3b mutant model of autism [Texte imprimé et/ou numérique] / D. M. JAMES, Auteur ; R. A. KOZOL, Auteur ; Y. KAJIWARA, Auteur ; A. L. WAHL, Auteur ; E. C. STORRS, Auteur ; Joseph D. BUXBAUM, Auteur ; M. KLEIN, Auteur ; B. MOSHIREE, Auteur ; J. E. DALLMAN, Auteur . - 3 p. Langues : Anglais ( eng) in Molecular Autism > 10 (2019) . - 3 p.
| Mots-clés : |
*Digestive transit *Enteroendocrine *Peristaltic rate *Phelan-McDermid syndrome approved by the Institutional Animal Care and Use Committee of University of Miami.The authors declare that they have no competing interests.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
| Index. décimale : |
PER Périodiques |
| Résumé : |
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 (shank3abDeltaC). Because PMS is caused by SHANK3 haploinsufficiency, we assessed the digestive tract (DT) structure and function in zebrafish shank3abDeltaC (+/-) 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 shank3abDeltaC (+/-) mutants. Rescue injections of mRNA encoding the longest human SHANK3 isoform into shank3abDeltaC (+/-) 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 shank3abDeltaC (+/-) and shank3abDeltaC (-/-) mutants (p < 0.05) while enteric neuron counts and overall structure of the DT epithelium, including goblet cell number, were unaffected in shank3abDeltaC (+/-) 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. |
| En ligne : |
https://dx.doi.org/10.1186/s13229-018-0250-4 |
| Permalink : |
https://www.cra-rhone-alpes.org/cid/opac_css/index.php?lvl=notice_display&id=389 |
|
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