Human Molecular Genetics Advance Access published online on April 27, 2007
Human Molecular Genetics, doi:10.1093/hmg/ddm106
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Identification of a novel role of ZIC3 in regulating cardiac development
1 Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 2 Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA 3 Institute of Biosciences and Technology, Texas A&M University System Health Science Center, 2121 West Holcombe Boulevard, Houston, TX 77030, USA
* Correspondence should be addressed to: John W. Belmont, M.D., Ph.D., Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 Tel: (713)-798-4634, Fax: (713)-798-8142, E-mail: jbelmont{at}bcm.tmc.edu
Received February 12, 2006; Revised April 11, 2007; Accepted April 17, 2007
Mutations in ZIC3 cause X-linked heterotaxy, a disorder characterized by abnormal lateralization of normally asymmetric thoracic and abdominal organs. Animal models demonstrate an early role for ZIC3 in embryonic left-right patterning. ZIC3 mutations have also been described in patients with isolated cardiovascular malformations. We wished to address the hypothesis that ZIC3 has plieotropic effects in development and may regulate cardiac development independent of its role in left-right patterning. We observed significantly reduced expression of several markers of cardiac lineage commitment in Zic3null/y ES cells including atrial natriuretic factor (ANF), Nkx2.5, and Tbx5. Likewise, ANF expression - a molecular marker of trabecular myocardium and a direct target of multiple cardiac-specific transcription factors - was severely reduced in E9.5 Zic3 null hearts. Trabecular myocardium was reduced in these embryos. This finding was similar to that observed in embryos with cardiac-specific ablation of serum response factor (SRF), a direct transcriptional regulator of ANF expression. While ZIC3 by itself had no effect on the ANF promoter, it could bind to and inhibit a cardiac 
-actin promoter through its zinc finger domains. We observed that ZIC3 could function as a coactivator of SRF on both cardiac -actin and ANF promoters. The zinc fingers of ZIC3 and the MADS box motif of SRF were found to mediate their physical and functional interactions. These findings reveal a novel role of ZIC3 in regulating cardiac gene expression and may explain, in part, the association of ZIC3 mutation with cardiovascular malformations.