Mcm5 Represses Endodermal Migration through Cxcr4a-itgb1b Cascade Instead of Cell Cycle Control
Yu Zhang,
Jiamin Xia,
Min Liu,
Bingyu Chen,
Min Yang,
Xiaoping Yu,
Yu Ou,
Shurong Li,
Xindong Liu,
Yi Feng,
Bingyin Su,
Sizhou Huang
Affiliations
Yu Zhang
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Jiamin Xia
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Min Liu
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Bingyu Chen
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Min Yang
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Xiaoping Yu
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Yu Ou
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Shurong Li
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Xindong Liu
Department of Neurology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu 610051, China
Yi Feng
Centre for Inflammation Research, Queen’s Medical Research Institute, University of Edinburgh, 47 Little France Crescent, Edinburgh EH16 4TJ, UK
Bingyin Su
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Sizhou Huang
Development and Regeneration Key Laboratory of Sichuan Province, Department of Anatomy and Histology and Embryology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu 610500, China
Minichromosome maintenance protein 5 (MCM5) is a critical cell cycle regulator; its role in DNA replication is well known, but whether it is involved in the regulation of organogenesis in a cell cycle-independent way, is far from clear. In this study, we found that a loss of mcm5 function resulted in a mildly smaller liver, but that mcm5 overexpression led to liver bifida. Further, the data showed that mcm5 overexpression delayed endodermal migration in the ventral–dorsal axis and induced the liver bifida. Cell cycle analysis showed that a loss of mcm5 function, but not overexpression, resulted in cell cycle delay and increased cell apoptosis during gastrulation, implying that liver bifida was not the result of a cell cycle defect. In terms of its mechanism, our data proves that mcm5 represses the expression of cxcr4a, which sequentially causes a decrease in the expression of itgb1b during gastrulation. The downregulation of the cxcr4a-itgb1b cascade leads to an endodermal migration delay during gastrulation, as well as to the subsequent liver bifida during liver morphogenesis. In conclusion, our results suggest that in a cell cycle-independent way, mcm5 works as a gene expression regulator, either partially and directly, or indirectly repressing the expression of cxcr4a and the downstream gene itgb1b, to coordinate endodermal migration during gastrulation and liver location during liver organogenesis.
