Cooperative and antagonistic interactions between Sall4 and Tbx5 pattern the mouse limb and heart.
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.
Koshiba-Takeuchi
Kazuko
K
Programs in Cardiovascular Research, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada.
Takeuchi
Jun K
JK
Arruda
Eric P
EP
Kathiriya
Irfan S
IS
Mo
Rong
R
Hui
Chi-chung
CC
Srivastava
Deepak
D
Bruneau
Benoit G
BG
D000818:Animals; D009320:Atrial Natriuretic Factor; D019521:Body Patterning; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005121:Extremities / Q000196:embryology*; D051526:Fibroblast Growth Factor 10 / Q000235:genetics / Q000378:metabolism; D005552:Forelimb / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D006321:Heart / Q000196:embryology*; D006330:Heart Defects, Congenital; D017880:Limb Deformities, Congenital; D051379:Mice; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D011498:Protein Precursors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C496464:Fgf10 protein, mouse; D051526:Fibroblast Growth Factor 10; C431578:Nppa protein, mouse; D011498:Protein Precursors; D012333:RNA, Messenger; C509167:Sall4 protein, mouse; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; C103177:Tbx4 protein, mouse; D014157:Transcription Factors; D020098:Natriuretic Peptide, C-Type; D009320:Atrial Natriuretic Factor