title: Zebrafish cul4a, but not cul4b, modulates cardiac and forelimb development by upregulating tbx5a expression.
abstract: CUL4A and CUL4B are closely related cullin family members and can each assemble a Cullin-RING E3 ligase complex (CRL) and participate in a variety of biological processes. While the CRLs formed by the two cullin members may have common targets, the two appeared to have very different consequences when mutated or disrupted in mammals. We here investigated the roles of cul4a and cul4b during zebrafish embryogenesis by using the morpholino knockdown approach. We found that cul4a is essential for cardiac development as well as for pectoral fin development. Whereas cul4a morphants appeared to be unperturbed in chamber specification, they failed to undergo heart looping. The failures in heart looping and pectoral fin formation in cul4a morphants were accompanied by greatly reduced proliferation of cardiac cells and pectoral fin-forming cells. We demonstrated that tbx5a, a transcription factor essential for heart and limb development, is transcriptionally upregulated by cul4a and mediates the function of cul4a in cardiac and pectoral fin development. In contrast to the critical importance of cul4a, cul4b appeared to be dispensable for zebrafish development and was incapable of compensating for the loss of cul4a. This work provides the first demonstration of an essential role of cul4a, but not cul4b, in cardiac development and in the regulation of tbx5a in zebrafish. These findings justify exploring the functional role of CUL4A in human cardiac development.
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Zhao
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Baichun
authors.initials: B
authors.lastname: Jiang
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Huili
authors.initials: H
authors.lastname: Hu
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Fei
authors.initials: F
authors.lastname: Mao
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Mi
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Li
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China.
authors.forename: Qiji
authors.initials: Q
authors.lastname: Liu
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China yxg8@sdu.edu.cn shaochangshun@sdu.edu.cn.
authors.forename: Changshun
authors.initials: C
authors.lastname: Shao
authors.affiliation: The Key Laboratory of Experimental Teratology, Ministry of Education and Institute of Molecular Medicine and Genetics, Shandong University School of Medicine, Jinan, Shandong 250012, China yxg8@sdu.edu.cn shaochangshun@sdu.edu.cn.
authors.forename: Yaoqin
authors.initials: Y
authors.lastname: Gong
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D044842:Cullin Proteins / Q000378:metabolism*; D005552:Forelimb / Q000254:growth & development*; D018507:Gene Expression Regulation, Developmental; D055785:Gene Knockdown Techniques; D006321:Heart / Q000254:growth & development*; D006330:Heart Defects, Congenital / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism; D029961:Zebrafish Proteins / Q000378:metabolism*
chemical_list: C000599554:CUL4B protein, zebrafish; C000599553:CUL4a protein, zebrafish; D044842:Cullin Proteins; D020825:T-Box Domain Proteins; C103172:T-box transcription factor 5; D029961:Zebrafish Proteins