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
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.
Available from: Andrea Barbuti
- "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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ABSTRACT: Since the first reports on the isolation and differentiation of stem cells, and in particular since the early success in driving these cells down a cardiac lineage, there has been interest in the potential of such preparations in cardiac regenerative therapy. Much of the focus of such research has been on improving mechanical function after myocardial infarction; however, electrophysiologic studies of these preparations have revealed a heterogeneous mix of action potential characteristics, including some described as "pacemaker" or "nodal-like," which in turn led to interest in the therapeutic potential of these preparations in the treatment of rhythm disorders; several proof-of-concept studies have used these cells to create a biologic alternative to electronic pacemakers. Further, there are additional potential applications of a preparation of pacemaker cells derived from stem cells, for example, in high-throughput screens of new chronotropic agents. All such applications require reasonably efficient methods for selecting or enriching the "nodal-like" cells, however, which in turn depends on first defining what constitutes a nodal-like cell since not all pacemaking cells are necessarily of nodal lineage. This review discusses the current state of the field in terms of characterizing sinoatrial-like cardiomyocytes derived from embryonic and induced pluripotent stem cells, markers that might be appropriate based on the current knowledge of the gene program leading to sinoatrial node development, what functional characteristics might be expected and desired based on studies of the sinoatrial node, and recent efforts at enrichment and selection of nodal-like cells.
Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.
Pharmacological reviews 04/2015; 67(2):368-388. DOI:10.1124/pr.114.009597 · 17.10 Impact Factor
Available from: Herbert Steinbeisser
- "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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ABSTRACT: The heart’s rhythm is initiated and regulated by a group of specialized cells in the sinoatrial node (SAN), the primary pacemaker of the heart. Abnormalities in the development of the SAN can result in irregular heart rates (arrhythmias). Although several of the critical genes important for SAN formation have been identified, our understanding of the transcriptional network controlling SAN development remains at a relatively early stage. The homeodomain transcription factor Shox2 is involved in the specification and patterning of the SAN. While the Shox2 knockout in mice results in embryonic lethality due to severe cardiac defects including improper SAN development, Shox2 knockdown in zebrafish causes a reduced heart rate (bradycardia). In order to gain deeper insight into molecular pathways involving Shox2, we compared gene expression levels in right atria of wildtype and Shox2−/− hearts using microarray experiments and identified the LIM homeodomain transcription factor Islet1 (Isl1) as one of its putative target genes. The downregulation of Isl1 expression in Shox2−/− hearts was confirmed and the affected region narrowed down to the SAN by whole-mount in situ hybridization. Using luciferase reporter assays and EMSA studies, we identified two specific SHOX2 binding sites within intron 2 of the ISL1 locus. We also provide functional evidence for Isl1 as a transcriptional target of Shox2 by rescuing the Shox2-mediated bradycardia phenotype with Isl1 using zebrafish as a model system. Our findings demonstrate a novel epistatic relationship between Shox2 and Isl1 in the heart with important developmental consequences for SAN formation and heart beat.
Electronic supplementary material
The online version of this article (doi:10.1007/s00395-013-0339-z) contains supplementary material, which is available to authorized users.
Archiv für Kreislaufforschung 03/2013; 108(2):339. DOI:10.1007/s00395-013-0339-z · 5.41 Impact Factor
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ABSTRACT: The evolution of the web triggered XML and web services which pave the way for world-wide information integration and service integration. Web 2.0 concepts and technologies further enriched community based web services. Now with debut of virtual world, there come the opportunities of new types of services with which services providers and services consumers could interact in immersive services environments. Virtual services or 3D services provide new service opportunities that existing web services cannot provide. In this paper, we compare the interaction patterns for web services and virtual services. We propose an architecture for virtual services and list its implications for new business models.
Services Computing, 2007. SCC 2007. IEEE International Conference on; 08/2007
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