The Hand1 transcription factor functions as a homodimer during mouse development

Hu, Dong; Scott, Ian C.; Geary, Colleen; Zhao, Xiang; Cross, James C.

doi:10.1016/j.ydbio.2006.04.134

Cited by 2 publications

(1 citation statement)

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“…Moreover, an additional consideration is whether, at high concentrations, specificity of Hand1 downstream effects may be lost resulting in an impact on nonendogenous Hand1 target genes. Although Hand1 functions as a heterodimer with E-factors in vitro, according to the classic bHLH 4603 RESEARCH ARTICLE Hand1 function in the developing heart paradigm (Firulli et al, 2000;Scott et al, 2000), it can also function as a homodimer (Hill and Riley, 2004;Scott et al, 2000) and, indeed, a tethered Hand1 homodimer allele, generated by homologous recombination in ES cells, can rescue the Hand1-null phenotype (Hu et al, 2006). Therefore, a dominant-negative effect on heterodimer formation can be ruled out as almost certainly lacking functional significance in vivo.…”

Section: Discussionmentioning

confidence: 99%

Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart

Risebro¹,

Smart²,

Dupays³

et al. 2006

Development

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The precise origins of myocardial progenitors and their subsequent contribution to the developing heart has been an area of considerable activity within the field of cardiovascular biology. How these progenitors are regulated and what signals are responsible for their development are, however,much less well understood. Clearly, not only is there a need to identify factors that regulate the transition from proliferation of cardioblasts to differentiation of cardiac muscle, but it is also necessary to identify factors that maintain an adequate pool of undifferentiated myocyte precursors as a prerequisite to preventing organ hypoplasia and congenital heart disease. Here, we report how upregulation of the basic helix-loop-helix (bHLH)transcription factor Hand1, restricted exclusively to Hand1-expressing cells, brings about a significant extension of the heart tube and extraneous looping caused by the elevated proliferation of cardioblasts in the distal outflow tract. This activity is independent of the further recruitment of extracardiac cells from the secondary heart field and permissive for the continued differentiation of adjacent myocardium. Culture studies using embryonic stem (ES) cell-derived cardiomyocytes revealed that,in a Hand1-null background, there is significantly elevated cardiomyocyte differentiation, with an apparent default mesoderm pathway to a cardiomyocyte fate. However, Hand1 gain of function maintains proliferating precursors resulting in delayed and significantly reduced cardiomyocyte differentiation that is mediated by the prevention of cell-cycle exit, by G1 progression and by increased cell division. Thus, this work identifies Hand1 as a crucial cardiac regulatory protein that controls the balance between proliferation and differentiation in the developing heart, and fills a significant gap in our understanding of how the myocardium of the embryonic heart is established.

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Section: Discussionmentioning

confidence: 99%

Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart

Risebro¹,

Smart²,

Dupays³

et al. 2006

Development

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Mutations within Helix I of Twist1 Result in Distinct Limb Defects and Variation of DNA Binding Affinities

Firulli

Redick

Conway

2007

Journal of Biological Chemistry

121

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Twist1 is a basic helix-loop-helix (bHLH) factor that plays an important role in limb development. Haploinsufficiency of Twist1 results in polydactyly via the inability of Twist1 to antagonistically regulate the related factor Hand2. The mechanism modulating Twist1-Hand2 antagonism is via phosphoregulation of conserved threonine and serine residues in helix I of the bHLH domain. Phosphoregulation alters the dimerization affinities for both proteins. Here we show that the expression of Twist1 and Twist1 phosphoregulation mutants results in distinct limb phenotypes in mice. In addition to dimer regulation, Twist1 phosphoregulation affects the DNA binding affinities of Twist1 in a partner-dependent and cis-element-dependent manner. In order to gain a better understanding of the specific Twist1 transcriptional complexes that function during limb morphogensis, we employ a series of Twist1-tethered dimers that include the known Twist1 partners, E12 and Hand2, as well as a tethered Twist1 homodimer. We show that these dimers behave in a manner similar to monomerically expressed bHLH factors and result in distinct limb phenotypes that correlate well with those observed from the limb expression of Twist1 and Twist1 phosphoregulation mutants. Taken together, this study shows that the Twist1 dimer affinity for a given partner can modulate the DNA binding affinity and that Twist1 dimer choice determines phenotypic outcome during limb development.Members of the Twist family of bHLH 2 proteins are evolutionarily conserved transcription factors that play fundamental roles in the normal development of a number of tissues, including extraembryonic membranes, teeth, jaw, heart, and limbs (1-3). Although bHLH/helix-loop-helix proteins can be organized into five groups, bHLH factors can be generally classified into two groups: the ubiquitously expressed E-proteins (class A) and the tissue-specific/restricted bHLH factors (class B) (for a review, see Ref. 4). The classic model for bHLH function is that a heterodimer containing a member from class A and a member from class B interacts via the amphipathic ␣-helices. This interaction juxtaposes the basic domains of both proteins, such that a DNA binding domain is formed that recognizes a DNA cis-element termed an E-box (CANNTG) (4). The requirement for class A/class B heterodimerization for many bHLH factors is well established, and in the case of the skeletal myogenic bHLH factors (MyoD1, Myogenin, Myf5, and Mrf4), heterodimerization is critical for proper biological function (4, 5). Other class B factors, such as members of the Twist family of bHLH proteins, not only function as heterodimers with E-proteins but can also form homodimers and heterodimers with other class B bHLH proteins (1-3, 6). It is thought that the control of bHLH dimerization is a mechanism that could control transcriptional response.Recently, we have shown that members of the Twist family of bHLH proteins contain an evolutionarily conserved threonine and serine within helix 1 that can be phosphoregulated by the a...

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The Hand1 transcription factor functions as a homodimer during mouse development

Cited by 2 publications

References 0 publications

Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart

Hand1 regulates cardiomyocyte proliferation versus differentiation in the developing heart

Mutations within Helix I of Twist1 Result in Distinct Limb Defects and Variation of DNA Binding Affinities

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