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Down syndrome mouse models have an abnormal enteric nervous system
Ellen M. Schill, … , Randall J. Roper, Robert O. Heuckeroth
Ellen M. Schill, … , Randall J. Roper, Robert O. Heuckeroth
Published April 18, 2019
Citation Information: JCI Insight. 2019;4(11):e124510. https://doi.org/10.1172/jci.insight.124510.
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Research Article Development Gastroenterology

Down syndrome mouse models have an abnormal enteric nervous system

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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 1

Tc1 and Ts65Dn mice have normal bowel colonization by ENS precursors at E12.5. (A–D) Ts65Dn and Tc1 euploid and trisomic E12.5 colon and distal small bowel were stained using Tuj1 antibody that marks early and mature neurons.

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Tc1 and Ts65Dn mice have normal bowel colonization by ENS precursors at ...
Maximum intensity projections of confocal Z-stacks are shown. White arrowheads indicate the position of most caudal TuJ1 immunoreactive neuronal process (green). Scale bar: 500 μm. (E–H) High-resolution images show HuC/D+ cell bodies (red) in hindgut in Ts65Dn (E and F) and Tc1 (G and H) lineage mice. Scale bar: 100 μm. (I and J) Percentage of colon colonized by ENCDC relative to total colon length for Ts65Dn (I; P = 0.653, Mann-Whitney rank sum test [MWRST], n = 9 [WT] and 10 [Ts65Dn]) and Tc1 (J; P = 0.24, t test, n = 9 [WT] and 11 [Tc1]) mice. (K and L) Mean HuC/D+ neuron density in most distal 500 μm of colonized bowel for Ts65Dn (K, P = 0.76; t test, n = 3 [WT], n = 7 [Ts65Dn]) and Tc1 (L, P = 0.94, t test, n = 7 [WT], n = 8 [Tc1]) mice. (M–O) Small bowel slices from E12.5 Ts65Dn and Tc1 mice were plated on fibronectin-treated chamber slides. GDNF was added 4 hours later. After an additional 16 hours in GDNF-containing media, slices were fixed and the distance from the farthest-migrated ENCDC to the slice edge (yellow line) was measured and averaged over 4 quadrants. (M) Representative image from slice culture after staining for RET (to identify ENCDC, red), phalloidin (which stains F-actin, green), and DAPI (nuclear stain, blue). (N and O) Ts65Dn (N, P = 0.436, MWRST, n = 26 [euploid] and 52 [Ts65Dn]) and Tc1 (O, P = 0.385, t test, n = 21 [euploid] and 35 [Tc1]) animals had similar ENCDC migration distance to euploid animals. (P) Ret heterozygosity did not affect migration of Ts65Dn ENCDC (P = 0.38, ANOVA, n = 5 [Euploid, Ret+/+], n = 5 [Ts65Dn, Ret+/+], and n = 4 [Ts65Dn, Ret+/–]).

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