The pattern of congenital heart defects arising from reduced Tbx5 expression is altered in a Down syndrome mouse model

BMC Developmental Biology

Roger H. Reeves⁴  Sally A. Camper³  Ivan P. Moskowitz²  Huiqing Li¹  Jeffrey D. Steimle²  Peter Gergics³  Renita C. Polk⁴ 

[1] Department of Physiology at Johns Hopkins, Biophysics 201, 725 N. Wolfe St., Baltimore 21205, MD, USA;Departments of Pediatrics, Pathology and Human Genetics, University of Chicago, Chicago, IL, USA;Department of Human Genetics, School of Medicine, University of Michigan, Ann Arbor, MI, USA;McKusick Nathans Institute for Genetic Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, USA

关键词: Trisomy;    Down syndrome;    Congenital heart defect;    Heart development;   

Others  :  1224003
DOI  :  10.1186/s12861-015-0080-y

 received in 2015-02-06, accepted in 2015-07-07,  发布年份 2015

【 摘 要 】

Background

Nearly half of all individuals with Down Syndrome (DS) have some type of congenital heart defect (CHD), suggesting that DS sensitizes to CHD but does not cause it. We used a common mouse model of DS, the Ts65Dn mouse, to study the contribution of Tbx5, a known modifier of CHD, to heart defects on a trisomic backgroun. Mice that were heterozygous for a Tbx5 null allele were crossed with Ts65Dn mice. Thoraxes of progeny were fixed in 10% formalin, embedded in paraffin, and sectioned for analysis of CHD. Gene expression in embryonic hearts was examined by quantitative PCR and in situ hybridization. A TBX5 DNA binding site was verified by luciferase assays.

Methods

Mice that were heterozygous for a Tbx5 null allele were crossed with Ts65Dn mice. Thoraxes of progeny were fixed in 10 % formalin, embedded in paraffin, and sectioned for analysis of CHD. Gene expression in embryonic hearts was examined by quantitative PCR and in situ hybridization. A TBX5 DNA binding site was verified by luciferase assays.

Results

We crossed mice that were heterozygous for a Tbx5 null allele with Ts65Dn mice. Mice that were trisomic and carried the Tbx5 mutation (Ts65Dn;Tbx5 ^+/− ) had a significantly increased incidence of overriding aorta compared to their euploid littermates. Ts65Dn;Tbx5 ^+/− mice also showed reduced expression of Pitx2, a molecular marker for the left atrium. Transcript levels of the trisomic Adamts1 gene were decreased in Tbx5 ^+/− mice compared to their euploid littermates. Evidence of a valid binding site for TBX5 upstream of the trisomic Adamts1 locus was also shown.

Conclusion

Haploinsufficiency of Tbx5 and trisomy affects alignment of the aorta and this effect may stem from deviations from normal left-right patterning in the heart. We have unveiled a previously unknown interaction between the Tbx5 gene and trisomy, suggesting a connection between Tbx5 and trisomic genes important during heart development.

【 授权许可】

   
2015 Polk et al.

【 图 表 】

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