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Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart

Abstract

Human mutations in TBX5, a gene encoding a T-box transcription factor, and SALL4, a gene encoding a zinc-finger transcription factor, cause similar upper limb and heart defects. Here we show that Tbx5 regulates Sall4 expression in the developing mouse forelimb and heart; mice heterozygous for a gene trap allele of Sall4 show limb and heart defects that model human disease. Tbx5 and Sall4 interact both positively and negatively to finely regulate patterning and morphogenesis of the anterior forelimb and heart. Thus, a positive and negative feed-forward circuit between Tbx5 and Sall4 ensures precise patterning of embryonic limb and heart and provides a unifying mechanism for heart/hand syndromes.

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Figure 1: Sall4 and Tbx5 expression in mouse development.
Figure 2: Tbx5 regulates Sall4 expression in forelimb and in heart.
Figure 3: Limb defects in Sall4GT/+ mice.
Figure 4: Genetic interaction between Tbx5 and Sall4 in patterning the forelimb.
Figure 5: Sall4 and Tbx5 regulate heart patterning.
Figure 6: Altered gene expression in mutant hearts.
Figure 7: Sall4 and Tbx5 interact to synergistically activate the Fgf10 promoter.
Figure 8: Cooperative and counteracting interactions between Sall4 and Tbx5 on cardiac promoters.

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Acknowledgements

We are grateful to A. Mori for help with statistics and quantitative RT-PCR. We also thank V. Christoffels, M. Nemer and T. Ogura for expression vectors and reporter constructs, and A. Brown, D. Duboule, M. Logan, G. Martin and C. Oka for in situ probes. This work was supported by grants from the Canadian Institutes of Health Research (B.G.B., C.c.H), the Heart and Stroke Foundation of Ontario (B.G.B.) and the March of Dimes Birth Defects Foundation (B.G.B.). K.K.-T. was supported by the Uehara Memorial Foundation. J.K.T holds a long-term fellowship from the Human Frontiers Science Program and was partly supported by the Mochida Memorial Foundation for Medical and Pharmaceutical Research. B.G.B. holds a Canada Research Chair in Developmental Cardiology.

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Correspondence to Benoit G Bruneau.

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Supplementary information

Supplementary Fig. 1

Schematic of Sall4 alleles. (PDF 179 kb)

Supplementary Fig. 2

Patterning defects in Tbx5−/+ limbs. (PDF 425 kb)

Supplementary Fig. 3

Nuclear localization of Sall4 proteins. (PDF 307 kb)

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Koshiba-Takeuchi, K., Takeuchi, J., Arruda, E. et al. Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart. Nat Genet 38, 175–183 (2006). https://doi.org/10.1038/ng1707

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