Mcm5 Represses Endodermal Migration through Cxcr4a-itgb1b Cascade Instead of Cell Cycle Control

Abstract

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.

Amd1-skp2 cascade regulates hepatocyte proliferation during liver growth and hepatocellular carcinoma development in zebrafish

“…One color in situ hybridization was performed as described in a previous study (Liu et al, 2019). The previous probes fabp10, prox1, hhex, and fabp2 were used as described in previous reports (Zhang et al, 2022). The CDs of amd1 and skp2 were amplified using PCR and cloned into the vector pcs2 + , then linearized the plasmids and synthesized the individual antisense probe as previously reported (Zhang et al, 2022).…”

“…The previous probes fabp10, prox1, hhex, and fabp2 were used as described in previous reports (Zhang et al, 2022). The CDs of amd1 and skp2 were amplified using PCR and cloned into the vector pcs2 + , then linearized the plasmids and synthesized the individual antisense probe as previously reported (Zhang et al, 2022). Two color in situ hybridization was performed as described in a previous study (Dunn et al, 2022).…”

Enhanced MCM5 Level Predicts Bad Prognosis in Acute Myeloid Leukemia

“…Microchromosome maintenance protein 5 (MCM5) is a key cell cycle regulator located on chromosome 22Q13.1 [ 12 ], whose role in DNA replication is verified [ 13 ]. MCM5 is a DNA licensing factor as an ingredient of the MCM2-7 complex, a putative replicative helicase vital for the initiation and extension of "once per cell cycle" DNA replication in eukaryotic cells [ 14 , 15 ].…”

MCM5 mutation leads to silence of Stat1-bcl2 and accelerates the apoptosis of immature T lymphocytes with DNA damage

“…MCM5 is a member of the crucial component of DNA replication licensing system and MCM5 loss leads to DNA duplication defects 28 . Previous work demonstrated that the number of MCM5 is excess over that of replication origins 29 and the excess MCM5 plays a critical role in regulation of gene transcription during embryonic development 30 . Here, we identi ed that, mcm5 loss disturbed DNA duplication of immature T lymphocyte and sequentially led to up-regulation of p53 signaling, which resulting in immature T lymphocyte apoptosis.…”