Dataset Information

Twist1 function in endocardial cushion cell proliferation, migration, and differentiation during heart valve development.

ABSTRACT: Twist1 is a bHLH transcription factor that regulates cell proliferation, migration, and differentiation in embryonic progenitor cell populations and transformed tumor cells. While much is known about Twist1's function in a variety of mesenchymal cell types, the role of Twist1 in endocardial cushion cells is unknown. Twist1 gain and loss of function experiments were performed in primary chicken endocardial cushion cells in order to elucidate its role in endocardial cushion development. These studies indicate that Twist1 can induce endocardial cushion cell proliferation as well as promote endocardial cushion cell migration. Furthermore, Twist1 is subject to BMP regulation and can induce expression of cell migration marker genes including Periostin, Cadherin 11, and Mmp2 while repressing markers of valve cell differentiation including Aggrecan. Previously, Tbx20 has been implicated in endocardial cushion cell proliferation and differentiation, and in the current study, Tbx20 also promotes cushion cell migration. Twist1 can induce Tbx20 expression, while Tbx20 does not affect Twist1 expression. Taken together, these data indicate a role for Twist1 upstream of Tbx20 in promoting cell proliferation and migration and repressing differentiation in endocardial cushion cells during embryonic development.

SUBMITTER: Shelton EL

PROVIDER: S-EPMC2413172 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Twist1 function in endocardial cushion cell proliferation, migration, and differentiation during heart valve development.

Shelton Elaine L EL Yutzey Katherine E KE

Developmental biology 20080229 1

Twist1 is a bHLH transcription factor that regulates cell proliferation, migration, and differentiation in embryonic progenitor cell populations and transformed tumor cells. While much is known about Twist1's function in a variety of mesenchymal cell types, the role of Twist1 in endocardial cushion cells is unknown. Twist1 gain and loss of function experiments were performed in primary chicken endocardial cushion cells in order to elucidate its role in endocardial cushion development. These stud ...[more]

PMID: 18353304

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Project description:Function of the heart begins long before its formation is complete. Analyses in mouse and zebrafish have shown that myocardial function is not required for early steps of organogenesis, such as formation of the heart tube or chamber specification. However, whether myocardial function is required for later steps of cardiac development, such as endocardial cushion (EC) formation, has not been established. Recent technical advances and approaches have provided novel inroads toward the study of organogenesis, allowing us to examine the effects of both genetic and pharmacological perturbations of myocardial function on EC formation in zebrafish. To address whether myocardial function is required for EC formation, we examined silent heart (sih(-/-)) embryos, which lack a heartbeat due to mutation of cardiac troponin T (tnnt2), and observed that atrioventricular (AV) ECs do not form. Likewise, we determined that cushion formation is blocked in cardiofunk (cfk(-/-)) embryos, which exhibit cardiac dilation and no early blood flow. In order to further analyze the heart defects in cfk(-/-) embryos, we positionally cloned cfk and show that it encodes a novel sarcomeric actin expressed in the embryonic myocardium. The Cfk(s11) variant exhibits a change in a universally conserved residue (R177H). We show that in yeast this mutation negatively affects actin polymerization. Because the lack of cushion formation in sih- and cfk-mutant embryos could be due to reduced myocardial function and/or lack of blood flow, we approached this question pharmacologically and provide evidence that reduction in myocardial function is primarily responsible for the defect in cushion development. Our data demonstrate that early myocardial function is required for later steps of organogenesis and suggest that myocardial function, not endothelial shear stress, is the major epigenetic factor controlling late heart development. Based on these observations, we postulate that defects in cardiac morphogenesis may be secondary to mutations affecting early myocardial function, and that, in humans, mutations affecting embryonic myocardial function may be responsible for structural congenital heart disease.

Dataset Information

Twist1 function in endocardial cushion cell proliferation, migration, and differentiation during heart valve development.

Publications

Twist1 function in endocardial cushion cell proliferation, migration, and differentiation during heart valve development.

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