Down syndrome mouse models have an abnormal enteric nervous system
Ellen M. Schill, Christina M. Wright, Alisha Jamil, Jonathan M. LaCombe, Randall J. Roper, Robert O. Heuckeroth
Ellen M. Schill, Christina M. Wright, Alisha Jamil, Jonathan M. LaCombe, Randall J. Roper, Robert O. Heuckeroth
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Research Article Development Gastroenterology

Down syndrome mouse models have an abnormal enteric nervous system

Abstract

Children with trisomy 21 (Down syndrome [DS]) have a 130-fold increased incidence of Hirschsprung disease (HSCR), a developmental defect in which the enteric nervous system (ENS) is missing from the distal bowel (i.e., distal bowel is aganglionic). Treatment for HSCR is surgical resection of aganglionic bowel, but many children have bowel problems after surgery. Postsurgical problems, such as enterocolitis and soiling, are especially common in children with DS. To determine how trisomy 21 affects ENS development, we evaluated the ENS in 2 DS mouse models, Ts65Dn and Tc1. These mice are trisomic for many chromosome 21 homologous genes, including Dscam and Dyrk1a, which are hypothesized to contribute to HSCR risk. Ts65Dn and Tc1 mice have normal ENS precursor migration at E12.5 and almost normal myenteric plexus structure as adults. However, Ts65Dn and Tc1 mice have markedly reduced submucosal plexus neuron density throughout the bowel. Surprisingly, the submucosal neuron defect in Ts65Dn mice is not due to excess Dscam or Dyrk1a, since normalizing copy number for these genes does not rescue the defect. These findings suggest the possibility that the high frequency of bowel problems in children with DS and HSCR may occur because of additional unrecognized problems with ENS structure.

Authors

Ellen M. Schill, Christina M. Wright, Alisha Jamil, Jonathan M. LaCombe, Randall J. Roper, Robert O. Heuckeroth

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Figure 4

Density of NADPH diaphorase+ neurons, calretinin+ neurons, and SOX10+ glia is normal in Ts65Dn adult small bowel.

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Density of NADPH diaphorase+ neurons, calretinin+ neurons, and SOX10+ gl...
Ts65Dn adult trisomic myenteric plexus from small bowel was stained with antibodies against HuC/D (A and E) and calretinin (B and F) and also stained using NADPH diaphorase histochemistry, which was pseudocolored blue to merge with fluorescent images (C and G). Merged images (D and H) show NADPHd+, calretinin+, and NADPHd–/calretinin– neurons. (I) Ts65Dn mice had normal ratios of specific neuron subtypes to total neurons (NADPH: P = 0.881, t test, n = 4 [euploid] and n = 4 [Ts65Dn]; calretinin: P = 0.839, t test, n = 4 [euploid] and n = 4 [Ts65Dn]; NADPHd–/calretinin–: P = 0.898, t test, n = 4 [euploid] and n = 4 [Ts65Dn]) and (J) absolute neuron density (NADPH: P = 0.986, t test, n = 4 [euploid] and n = 4 [Ts65Dn]; calretinin: P = 0.960, t test, n = 4 [euploid] and n = 4 [Ts65Dn]; NADPHd–/calretinin–: P = 0.961, t test, n = 4 [euploid] and n = 4 [Ts65Dn]). (K and L) Adult myenteric plexus from euploid and Ts65Dn mid-small intestine was stained with anti-SOX10 antibody and imaged using confocal Z-stacks. Maximum intensity projections are shown. (M) Ts65Dn and euploid animals did not differ in numbers of myenteric SOX10+ glia (P = 0.980, t test, n = 4 [euploid] and n = 3 [Ts65Dn]). Scale bar: 100 μM.