First published online April 27, 2005
Development 132, 1004e (2005)
© The Company of Biologists Limited
Tbx20: orchestrating heart development
Although 
1% of humans are born with structural heart malformations, we
know relatively little about the transcriptional programs that underpin the
complex, orchestrated process of heart development. Now three papers in
Development report that the T-box transcription factor Tbx20 occupies
a central position in the pathways that control heart lineage specification
and morphogenesis, from where it acts dose-dependently to influence embryonic
heart development and adult heart function. Richard Harvey's (see p.
2451) and Sylvia
Evans' (see p. 2475)
groups both used gene targeting in mice to investigate Tbx20's role
in cardiogenesis. Both report that Tbx20 null mice die in
mid-gestation with severely malformed, underdeveloped hearts in which heart
chamber formation had failed. Underlying these defects is a perturbed
transcriptional program that alters cell proliferation patterns, the expansion
of cardiac progenitors and the acquisition of tissue identity. In particular,
both teams found that Tbx2 – a transcriptional repressor that inhibits
chamber-specific gene expression programs in non-chamber heart tissue –
is inappropriately activated throughout the heart in Tbx20 null mice.
These and other data lead Harvey and co-workers to propose that hierarchical,
repressive interactions between Tbx20 and other T-box factors underlie the
early lineage split between chamber and non-chamber myocardium on which
subsequent heart morphogenesis depends. These conclusions are strengthened by
the findings of Evans' team, who show that Tbx2 is a direct target of Tbx20.
Moreover, they report that Tbx2 directly binds to Nmyc1, which it represses in
vitro and which is required for early myocardial proliferation. Nmyc1
expression is also downregulated in Tbx20-/- mice. From
their findings, these authors conclude that Tbx20 regulates cell proliferation
in a region-specific manner by repressing Tbx2, which in turn represses
Nmyc1. Thus, these two studies reveal how Tbx20 co-ordinates the
transcriptional programs that control heart tissue specification and growth.
Harvey and co-workers' further finding that heart function is compromised in
adult Tbx20+/– mice adds additional complexity to
this picture. The dose-dependent effects of Tbx20 are elegantly expanded upon
by Benoit Bruneau and co-workers (see p.
2463). This group
knocked down Tbx20 in ES cells using RNAi, and then generated mouse
embryos from cell lines in which Tbx20 was expressed highly,
moderately or not at all. Their findings show that Tbx20 acts in a
dose-dependent manner during heart and motoneuron development – the
complete knockdown of Tbx20, for example, mirrors the null mutant,
while a mild knockdown causes right ventricle underdevelopment and persistent
truncus arteriosus, defects associated with human heart congenital conditions.
The breakdown of cardiac transcription factor networks also features in this
study. Specifically, this team found that Tbx20 might act synergistically with
the cardiac transcription factors Isl1 and Gata4 to activate Mef2c
and Nkx2. 5 expression – genes that are required for anterior
heart field formation, a region that gives rise to the heart's outflow tract
and ventricles. Together, these papers shed new light on how tissue
specification, morphogenesis and proliferation are co-ordinated in early heart
development by Tbx20, and provide new candidates for the study of both
congenital heart defects and adult cardiomyopathies.
Related articles in Development:
- Murine T-box transcription factor Tbx20 acts as a repressor during heart development, and is essential for adult heart integrity, function and adaptation
- Fiona A. Stennard, Mauro W. Costa, Donna Lai, Christine Biben, Milena B. Furtado, Mark J. Solloway, David J. McCulley, Christiana Leimena, Jost I. Preis, Sally L. Dunwoodie, David E. Elliott, Owen W. J. Prall, Brian L. Black, Diane Fatkin, and Richard P. Harvey
Development 2005 132: 2451-2462.
[Abstract]
[Full Text]
- Tbx20 dose-dependently regulates transcription factor networks required for mouse heart and motoneuron development
- Jun K. Takeuchi, Maria Mileikovskaia, Kazuko Koshiba-Takeuchi, Analeah B. Heidt, Alessandro D. Mori, Eric P. Arruda, Marina Gertsenstein, Romain Georges, Lorinda Davidson, Rong Mo, Chi-chung Hui, R. Mark Henkelman, Mona Nemer, Brian L. Black, Andras Nagy, and Benoit G. Bruneau
Development 2005 132: 2463-2474.
[Abstract]
[Full Text]
- T-box genes coordinate regional rates of proliferation and regional specification during cardiogenesis
- Chen-Leng Cai, Wenlai Zhou, Lei Yang, Lei Bu, Yibing Qyang, Xiaoxue Zhang, Xiaodong Li, Michael G. Rosenfeld, Ju Chen, and Sylvia Evans
Development 2005 132: 2475-2487.
[Abstract]
[Full Text]
