title: Functional redundancy between human SHOX and mouse Shox2 genes in the regulation of sinoatrial node formation and pacemaking function.
abstract: The homeodomain transcription factor Shox2 plays a crucial regulatory role in the development of sinoatrial node (SAN) by repressing the expression of Nkx2.5, as demonstrated by failed differentiation of SAN in Shox2 null mice. The SHOX (short stature homeobox) gene family consists of two closely related members, SHOX and SHOX2 in humans, but a SHOX ortholog does not exist in the mouse genome. These two genes exhibit overlapping and distinct expression patterns in many developing organs but whether they share functional redundancy is not known. In this study, we set to investigate possible functional redundancy between SHOX and SHOX2 in vitro and in vivo. We first showed that human SHOX and SHOX2 and mouse Shox2 possess similar transcriptional repressive activities in cell cultures, particularly the repressive effects on the Nkx2.5 promoter activity. We further created an SHOX/Shox2 knock-in mouse line (replacement of Shox2 with SHOX, referred as Shox2(KI/KI)). Mice carrying the hypomorphic Shox2(KI+Neo/KI+Neo) allele exhibit bradycardia and arrhythmia and die a few days after birth. However, mice carrying the Shox2(KI/KI) allele grow to adulthood. Physiological, histological, and molecular analyses demonstrate a fully developed SAN and normal pacemaking function in Shox2(KI/KI) mice. Our results demonstrate a functional redundancy between human SHOX and mouse Shox2 in the regulation of SAN formation and pacemaking function in addition to several other organs. The SHOX/Shox2 dose appears to be critical for normal pacemaking function.
authors: Department of Cell and Molecular Biology, Tulane University, New Orleans, Louisiana 70118, USA.
authors: Hongbing
authors: H
authors: Liu
authors: Chao-Hui
authors: CH
authors: Chen
authors: Ramón A
authors: RA
authors: Espinoza-Lewis
authors: Zhen
authors: Z
authors: Jiao
authors: Ivana
authors: I
authors: Sheu
authors: Xuefeng
authors: X
authors: Hu
authors: Minkui
authors: M
authors: Lin
authors: Yanding
authors: Y
authors: Zhang
authors: YiPing
authors: Y
authors: Chen
mesh_terms: D000483:Alleles; D000818:Animals; D001145:Arrhythmias, Cardiac / Q000378:metabolism; D004562:Electrocardiography / Q000379:methods; D005786:Gene Expression Regulation; D006321:Heart / Q000502:physiology*; D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008957:Models, Genetic; D000074122:Short Stature Homeobox Protein; D012849:Sinoatrial Node / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D000072576:Homeobox Protein Nkx-2.5; D018398:Homeodomain Proteins; C484469:Nkx2-5 protein, mouse; C106071:SHOX protein, human; D000074122:Short Stature Homeobox Protein; C484663:Shox2 protein, mouse; D014157:Transcription Factors