The Role of Shox2 in SAN Development and Function

Abstract

Embryonic development is a tightly regulated process, and many families of genes functions to provide a regulatory genetic network to achieve such a program. The homeobox genes are an extensive family that encodes transcription factors with a characteristic 60-amino acid homeodomain. Mutations in these genes or in the encoded proteins might result in structural malformations, physiological defects, and even embryonic death. Mutations in the short-stature homeobox gene (SHOX) is associated with idiopathic short stature in humans, as observed in patients with Turner syndrome and/or Leri-Weill dyschondrosteosis. A closely related human homolog, SHOX2, has not been linked to any syndrome or defect so far. In mice, a SHOX ortholog gene is not present in the genome; however, a true SHOX2 ortholog has been identified. Analyses of Shox2 knockout mouse models have showed crucial functions during embryonic development, including limb skeletogenesis, palatogenesis, temporomandibular joint formation, and cardiovascular development. During embryonic cardiac development, Shox2 is restrictedly expressed in the sinus venosus region, including the sinoatrial node (SAN) and the sinus valves. Shox2 null mutant is embryonically lethal due to cardiovascular defects, including a severely hypoplastic SAN and sinus valves attributed to a significantly decreased level of cell proliferation in addition to an abnormal low heartbeat rate (bradycardia). In addition, it has been demonstrated that Shox2 regulates a genetic network through the repression of Nkx2.5 to maintain the SAN fate and thus plays essential roles in its proper formation and differentiation.

Pitx2 -microRNA pathway that delimits sinoatrial node development and inhibits predisposition to atrial fibrillation

“…Although Shox2 is required for SAN development in mice, it has not yet been implicated in human heart disease. However, there are data indicating that Shox2 is a target for Tbx5 that has been implicated in human AF and prolonged PR interval through GWAS studies (31,32). Tbx3 has also been implicated in human PR interval prolongation in GWAS studies (32) and induces pacemaker properties in adult myocardium when misexpressed (33).…”

Promoter hypermethylation of SHOX2 and SEPT9 is a potential biomarker for minimally invasive diagnosis in adenocarcinomas of the biliary tract

“…As a transcriptional factor, SHOX2 is known to be involved in various embryonic developmental processes including limb formation and cardiac development [31–33]. Aberrant DNA methylation of SHOX2 has been extensively characterized as a biomarker for the diagnosis of lung cancer.…”

Replacing Shox2 with human SHOX leads to congenital disc degeneration of the temporomandibular joint in mice

“…In humans, mutations in SHOX have been associated with a series of short-stature conditions, including Turner syndrome, Leri-Weill dyschondrosteosis, and Langer dysplasia that exhibit abnormalities in the skeletal development (Bobick and Cobb., 2012; Hirschfeldova et al, 2012). While SHOX2 expression has been observed in the developing limbs in a complementary pattern to that of SHOX and in the developing heart of human embryo (Clement-Jones et al, 2000; Liu et al, 2011; 2012), there is no any known syndrome that has been linked to SHOX2 mutations thus far. In mice, targeted inactivation of Shox2 leads to severe defects in a number of developing organs including the limb, heart, palate, as well as the TMJ that exhibits dysplasia and ankylosis (Yu et al, 2005; 2007; Cobb et al, 2006; Blaschke et al, 2007; Gu et al, 2008).…”