Non-trisomic homeobox gene expression during craniofacial development in the Ts65Dn mouse model of Down syndrome

Abstract

Trisomy 21 in humans causes cognitive impairment, craniofacial dysmorphology, and heart defects collectively referred to as Down syndrome. Yet, the pathophysiology of these phenotypes is not well understood. Craniofacial alterations may lead to complications in breathing, eating, and communication. Ts65Dn mice exhibit craniofacial alterations that model Down syndrome including a small mandible. We show that Ts65Dn embryos at 13.5 days gestation (E13.5) have a smaller mandibular precursor but a normal sized tongue as compared to euploid embryos, suggesting a relative instead of actual macroglossia originates during development. Neurological tissues were also altered in E13.5 trisomic embryos. Our array analysis found 155 differentially expressed non-trisomic genes in the trisomic E13.5 mandible, including 20 genes containing a homeobox DNA binding domain. Additionally, Sox9, important in skeletal formation and cell proliferation, was upregulated in Ts65Dn mandible precursors. Our results suggest trisomy causes altered expression of non-trisomic genes in development leading to structural changes associated with DS. Identification of genetic pathways disrupted by trisomy is an important step in proposing rational therapies at relevant time points to ameliorate craniofacial abnormalities in DS and other congenital disorders.

Keywords: developmental delay disorders; experimental animal models; genotype-phenotype correlation; trisomy 21.

Fig. 1. Sox9 expression in the E13.5 Meckel's and hyoid cartilages

Sox9 expression was increased in theTs65Dn Meckel's cartilage (A) and hyoid cartilage (B) when compared to euploid littermate embryos. Average of nine sections from five euploid and eight sections from five trisomic embryos for Meckel's cartilage; and average of eight sections from four euploid and eight sections from five trisomic embryos for hyoid cartilage. Error bars indicate standard error (*p ≤ 0.05).