Down syndrome mouse models have an abnormal enteric nervous system

Area of Science:

• Developmental biology
• Genetics
• Neuroscience

Background:

• Children with Down syndrome (DS) exhibit a significantly higher incidence of Hirschsprung disease (HSCR).
• HSCR involves the absence of the enteric nervous system (ENS) in the distal bowel, leading to surgical intervention.
• Post-surgical complications are frequent in children with DS and HSCR, indicating underlying developmental complexities.

Purpose of the Study:

• To investigate the impact of trisomy 21 on the development of the enteric nervous system (ENS).
• To evaluate ENS structure in DS mouse models (Ts65Dn and Tc1) to understand HSCR risk factors.

Main Methods:

• Analysis of ENS development in Ts65Dn and Tc1 trisomy 21 mouse models.
• Assessment of enteric nervous system precursor migration and adult myenteric and submucosal plexus structure.
• Evaluation of the role of Dscam and Dyrk1a genes in ENS development by normalizing copy number.

Main Results:

• Ts65Dn and Tc1 mice displayed normal ENS precursor migration and largely normal adult myenteric plexus structure.
• A significant reduction in submucosal plexus neuron density was observed throughout the bowel in these DS models.
• The submucosal neuron defect was not rescued by normalizing Dscam or Dyrk1a gene copy numbers, suggesting other factors are involved.

Conclusions:

• Trisomy 21 impacts ENS development, specifically affecting submucosal plexus neuron density.
• The observed ENS defect in DS mouse models is independent of Dscam and Dyrk1a gene dosage.
• These findings suggest that unrecognized structural abnormalities in the ENS may contribute to the high frequency of bowel problems in children with DS and HSCR.