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Title: Zic3 is required in the extra-cardiac perinodal region of the lateral plate mesoderm for left-right patterning and heart development

Author
item JIANG, ZHENGXIN - Baylor College Of Medicine
item ZHU, LIRONG - Baylor College Of Medicine
item HU, LINGYUN - Baylor College Of Medicine
item SLESNICK, TIMOTHY - Baylor College Of Medicine
item PAUTLER, ROBIA - Baylor College Of Medicine
item JUSTICE, MONICA - Baylor College Of Medicine
item BELMONT, JOHN - Children'S Nutrition Research Center (CNRC)

Submitted to: Human Molecular Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 11/20/2012
Publication Date: 3/1/2013
Citation: Jiang, Z., Zhu, L., Hu, L., Slesnick, T.C., Pautler, R.G., Justice, M.J., Belmont, J.W. 2013. Zic3 is required in the extra-cardiac perinodal region of the lateral plate mesoderm for left-right patterning and heart development. Human Molecular Genetics. 22(5):879-889.

Interpretive Summary: Heart defects are common malformations that are the single largest contributors to infant mortality due to birth defects in the US. We are interested in the genetic causes of heart defects and how genetic factors and nutritional factors interact to cause birth defects. One of the known causes of heart defects is a mutation in a specific human gene (Zic3) which causes cardiovascular malformations. In this study we used genetically engineered mice to demonstrate Zic3. The results provide supporting evidence for a role of Zic3 in heart defects. This model supports the developmental model in which a small disturbance in an early stage embryo leads to a variety of complex heart malformations.

Technical Abstract: Mutations in ZIC3 cause human X-linked heterotaxy and isolated cardiovascular malformations. A mouse model with targeted deletion of Zic3 demonstrates an early role for Zic3 in gastrulation, CNS, cardiac and left-right axial development. The observation of multiple malformations in Zic3(null) mice and the relatively broad expression pattern of Zic3 suggest its important roles in multiple developmental processes. Here, we report that Zic3 is primarily required in epiblast derivatives to affect left-right patterning and its expression in epiblast is necessary for proper transcriptional control of embryonic cardiac development. However, cardiac malformations in Zic3 deficiency occur not because Zic3 is intrinsically required in the heart but rather because it functions early in the establishment of left-right body axis. In addition, we provide evidence supporting a role for Zic3 specifically in the perinodal region of the posterior lateral plate mesoderm for the establishment of laterality. These data delineate the spatial requirement of Zic3 during left-right patterning in the mammalian embryo, and provide basis for further understanding the molecular mechanisms underlying the complex interaction of Zic3 with signaling pathways involved in the early establishment of laterality.