The Role of Shox2 in SAN Development and Function

Department of Cell and Molecular Biology, Tulane University, New Orleans, LA 70118, USA.
Pediatric Cardiology (Impact Factor: 1.31). 02/2012; 33(6):882-9. DOI: 10.1007/s00246-012-0179-x
Source: PubMed


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.

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    • "This expression pattern also has been demonstrated during human embryonic development (Liu et al., 2012). Shox2, like Tbx18, has an expression pathway complementary to that of Nkx2.5, the best marker of the FHF that during development marks the whole heart, with the exception of the conduction system (Liu et al., 2012). Nkx2.5 expression turns on the genetic pathway, leading to cardiac chamber formation; it can bind to Cx40 and Nppa promoters and activate their expression (Hoogaars et al., 2004). "
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    • "So far, several transcription factors of the homeobox- and T-box gene families have been shown to be involved in cardiac conduction system specification, patterning, maturation, and function [17, 37]. Among these genes is the paired-related homeodomain transcription factor Shox2, which is known to play a crucial role in early cardiac formation, particularly in SAN development and specification [2, 11, 12, 30, 42]. Shox2 expression can first be detected in the posterior region of the primitive heart tube at murine embryonic stage E8.5 and as development progresses, Shox2 is specifically expressed in the sinus venosus myocardium comprising the SAN and the venous valves [2, 12]. "
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