TBX5 is required for embryonic cardiac cell cycle progression

Goetz, Sarah C.; Brown, Daniel D.; Conlon, Frank L.

doi:10.1242/dev.02420

Cited by 64 publications

(49 citation statements)

References 53 publications

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“…Both groups demonstrated a statistically significant enrichment in TBX5 binding sites in the TBX5 ChIP-peak regions (activated 4.88 × 10 −141 , repressed p = 1.29 × 10 −142 , KS test, Figure 3B). Genes repressed by TBX5 were enriched in pathways involved in cancer as well as cardiac diseases, while genes activated by TBX5 were enriched in pathways involved in cell cycle and DNA replication, a known function of TBX5 (Figure 3C) (Hatcher et al, 2001, Goetz et al, 2006). …”

Section: Resultsmentioning

confidence: 99%

The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation

et al. 2016

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SUMMARY Human mutations in the cardiac transcription factor gene TBX5 cause Congenital Heart Disease (CHD), however the underlying mechanism is unknown. We report characterization of the endogenous TBX5 cardiac interactome and demonstrate that TBX5, long considered a transcriptional activator, interacts biochemically and genetically with the Nucleosome Remodeling and Deacetylase (NuRD) repressor complex. Incompatible gene programs are repressed by TBX5 in the developing heart. CHD missense mutations that disrupt the TBX5-NuRD interaction cause depression of a subset of repressed genes. Furthermore, the TBX5-NuRD interaction is required for heart development. Phylogenetic analysis showed that the TBX5-NuRD interaction domain evolved during early diversification of vertebrates, simultaneous with the evolution of cardiac septation. Collectively, this work defines a TBX5-NuRD interaction essential to cardiac development and the evolution of the mammalian heart, and when altered may contribute to human CHD.

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Section: Resultsmentioning

confidence: 99%

The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation

et al. 2016

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“…Embryos were then processed and visualized by TEM as described previously (21). Briefly, embryos were post-fixed in ferrocyanide-reduced osmium and embedded in Spurr's epoxy resin.…”

Section: Methodsmentioning

confidence: 99%

Skeletal Muscle Differentiation and Fusion Are Regulated by the BAR-containing Rho-GTPase-activating Protein (Rho-GAP), GRAF1

Doherty

Lenhart

Cameron

et al. 2011

Journal of Biological Chemistry

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Although RhoA activity is necessary for promoting myogenic mesenchymal stem cell fates, recent studies in cultured cells suggest that down-regulation of RhoA activity in specified myoblasts is required for subsequent differentiation and myotube formation. However, whether this phenomenon occurs in vivo and which Rho modifiers control these later events remain unclear. We found that expression of the Rho-GTPase-activating protein, GRAF1, was transiently up-regulated during myogenesis, and studies in C2C12 cells revealed that GRAF1 is necessary and sufficient for mediating RhoA down-regulation and inducing muscle differentiation. Moreover, forced expression of GRAF1 in pre-differentiated myoblasts drives robust muscle fusion by a process that requires GTPase-activating protein-dependent actin remodeling and BAR-dependent membrane binding or sculpting. Moreover, morpholino-based knockdown studies in Xenopus laevis determined that GRAF1 expression is critical for muscle development. GRAF1-depleted embryos exhibited elevated RhoA activity and defective myofibrillogenesis that resulted in progressive muscle degeneration, defective motility, and embryonic lethality. Our results are the first to identify a GTPase-activating protein that regulates muscle maturation and to highlight the functional importance of BAR domains in myotube formation.Skeletal muscle development is a tightly regulated process involving the specification of mesodermal precursors into myoblasts and subsequent differentiation and fusion of these cells into multinucleated myotubes. Primary myogenesis is initiated in somites via the spatial and temporal expression of myogenic regulatory factors that include MyoD and Myf5, which are required for initial specification of skeletal myoblasts, and myogenin, MRF4, and myocyte-specific enhancer factors (MEF2a and MEF2c), which induce differentiation of these specified cells. Additional transcriptional control of skeletal muscle differentiation is imparted by serum-response factor, a MADS box-containing transcription factor that promotes both myoblast proliferation and expression of skeletal muscle marker genes (for review see Ref. 1).It is not completely clear how these myogenic regulatory factors are activated during development, but it is known that the small GTPase Rho (which can induce serum-response factordependent gene transcription) plays a role. RhoA was reported to both promote and interfere with the skeletal muscle differentiation program (for review see Ref.2). However, more recent studies in cultured cells suggest that RhoA activity must be tightly regulated in a finely coordinated time-dependent manner to ensure appropriate skeletal muscle formation (3-5). Specifically, these later studies showed that although RhoA activity is necessary for specification of myoblasts, down-regulation of RhoA activity in specified myoblasts is essential for subsequent cell cycle withdrawal, expression of skeletal muscle differentiation genes, and myotube fusion (i.e. secondary myogenesis). The mechanism by which ...

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“…To date, functionally confirmed direct targets of TBX5 are almost exclusively in genes implicated in cardiac proliferation, maturation, and function, including Nppa , Gja5 , and Scn5a (Arnolds et al, 2012; Bruneau et al, 2001; Goetz et al, 2006; Hatcher et al, 2001; Hiroi et al, 2001; Mori et al, 2006; Moskowitz et al, 2007, 2004; Puskaric et al, 2010; Xie et al, 2012). Interestingly, the direct targets mediating the morphogenesis requirement for TBX5 remain unknown.…”

Section: The Tbx5 Gene Regulatory Networkmentioning

confidence: 98%

“…TBX5 has long been known to act as a positive regulator of transcription in heart development and cardiomyocyte maturation (Bruneau et al, 2001; Goetz, Brown, & Conlon, 2006; Hiroi et al, 2001; Moskowitz et al, 2004). Some of the earliest identified direct targets of TBX5 were NPPA (encoding ANF) and GJA5 (encoding cx40), both of which are expressed in differentiating cardiomyocytes during development and are markers of cardiac chamber differentiation (Bruneau et al, 2001; Christoffels et al, 2000; Delorme et al, 1997; Hiroi et al, 2001).…”

Section: The Tbx5 Gene Regulatory Networkmentioning

confidence: 99%

Tbx5

Steimle

2017

Current Topics in Developmental Biology

135

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TBX5 is a member of the T-box transcription factor family and is primarily known for its role in cardiac and forelimb development. Human patients with dominant mutations in TBX5 are characterized by Holt–Oram syndrome, and show defects of the cardiac septa, cardiac conduction system, and the anterior forelimb. The range of cardiac defects associated with TBX5 mutations in humans suggests multiple roles for the transcription factor in cardiac development and function. Animal models demonstrate similar defects and have provided a useful platform for investigating the roles of TBX5 during embryonic development. During early cardiac development, TBX5 appears to act primarily as a transcriptional activator of genes associated with cardiomyocyte maturation and upstream of morphological signals for septation. During later cardiac development, TBX5 is required for patterning of the cardiac conduction system and maintenance of mature cardiomyocyte function. A comprehensive understanding of the integral roles of TBX5 throughout cardiac development and adult life will be critical for understanding human cardiac morphology and function.

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TBX5 is required for embryonic cardiac cell cycle progression

Cited by 64 publications

References 53 publications

The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation

The Cardiac TBX5 Interactome Reveals a Chromatin Remodeling Network Essential for Cardiac Septation

Skeletal Muscle Differentiation and Fusion Are Regulated by the BAR-containing Rho-GTPase-activating Protein (Rho-GAP), GRAF1

Tbx5

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