Paper 2. Mandel_2010

Paper 2. Mandel_2010 - RESEARCH ARTICLE 1919 Development...

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1919 RESEARCH ARTICLE INTRODUCTION A series of clinical studies has provided direct evidence of a role for T-box genes in heart development and human disease, as mutations in at least three T-box genes, TBX1 , TBX5 and TBX20 , have been linked to human congenital heart disease (CHD) (Papaioannou and Silver, 1998; Papaioannou, 2001; Prall et al., 2002; Packham and Brook, 2003; Ryan and Chin, 2003; Baldini, 2004; Showell et al., 2004; Mandel et al., 2005; Plageman and Yutzey, 2005; Stennard and Harvey, 2005; Hammer et al., 2008; Kirk et al., 2007; Liu et al., 2008; Qian et al., 2008). Specifically, mutations in TBX20 have been associated with a wide array of congenital abnormalities, including dilated cardiomyopathy (DCM), atrial septal defects (ASD) and mitral valve disease. Moreover, upregulation of TBX20 has been reported in patients with tetralogy of Fallot (Hammer et al., 2008; Kirk et al., 2007; Liu et al., 2008; Qian et al., 2008). These findings are consistent with studies of Tbx20 orthologs in a wide range of model systems, including mouse ( Tbx12/20 ) (Carson et al., 2000; Kraus et al., 2001), zebrafish ( Tbx20/HrT ) (Ahn et al., 2000; Griffin et al., 2000), chick (Iio et al., 2001) and Xenopus (Brown et al., 2003), which have shown a requirement for Tbx20 in a number of cardiac cellular processes. The effects of Tbx20 loss appear to be in part mediated through its endogenous role in restricting expression of Tbx2 , a T-box-containing protein required for the repression of chamber-specific genes (Singh et al., 2009). Despite the essential role of Tbx20 in cardiac development, little is known about the signal transduction pathways that function upstream to regulate Tbx20 expression in the developing heart. Members of the bone morphogenetic protein (BMP) family and their downstream mediators, the SMADs, have also been shown to be required for many cellular events in early heart development, including cardiac progenitor specification, proliferation and differentiation. The role of BMPs in cardiac development is evidenced by the cardiac-associated defects in mice mutant for components of the BMP pathway and by the observation that SMAD proteins, mediators of BMP signaling, are upregulated in response to cardiac stress or injury. However, identification of a specific cellular role for any single component of the BMP pathway in cardiac development is frequently confounded by genetic redundancy within the BMP and SMAD families, and by temporal and spatial differences in the activities of individual pathway components (for reviews, see Klaus and Birchmeier, 2009; Euler- Taimor and Heger, 2006; Wijk et al., 2007). An alternative means of dissecting the roles of BMPs in early heart development would be to identify the direct transcriptional targets of BMP signaling; however, the cardiac targets of the BMP pathway remain poorly characterized.
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This note was uploaded on 11/11/2010 for the course MCDB 112 taught by Professor Staff during the Spring '08 term at UCSB.

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Paper 2. Mandel_2010 - RESEARCH ARTICLE 1919 Development...

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