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PAR3-mediated coordination of hepatocyte proliferation, maturation, and architecture in liver development and regeneration

ABSTRACT: The liver’s ability to coordinate cell proliferation, polarization, and maturation with architectural assembly is fundamental to its metabolic functions and regenerative capacity. However, the mechanisms that integrate these processes remain incompletely understood. Using murine and human models, we show that hepatic polarity and bile canaliculi (BC) formation initiate at sites of cell division during the hepatoblast stage, and that BC elongation is temporally associated with oriented cell division during hepatocyte differentiation. This process involves PAR3- and YAP-dependent modulation of ERK/MAPK signaling. PAR3 forms a protein complex that localizes a subset of IQGAP1 to tight junctions, thereby restricting ERK/MAPK activation at the basolateral membrane. This regulation is required for efficient BC elongation and hepatocyte maturation. Together, these findings reveal a stage-dependent mechanism linking liver architecture to functional maturation and provide insights into liver development, regeneration, and potential therapeutic strategies for metabolic liver disease and liver failure.

ORGANISM(S): Mus Musculus

SUBMITTER: Chengran Xu

PROVIDER: PXD078219 | iProX | Sun May 10 00:00:00 BST 2026

REPOSITORIES: iProX

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Project description:Preimplantation development is a crucial step for successful implantation and pregnancy. Although both compaction and blastocyst formation have been extensively studied, mechanisms regulating early cell division stages before compaction have remained unclear. Here, we show that ERK MAP kinase function is required for early embryonic cell division and normal cell-cell adhesion before compaction. Our analysis demonstrates that inhibition of ERK activation in the late 2-cell stage embryos leads to a reversible arrest in G2 phase in the 4-cell stage. The G2 arrested, 4-cell stage embryos show weakened cell-cell adhesion as compared to control embryos. Remarkably, microarray analyses show that most of the programmed changes of upregulated and downregulated gene expression during the 4- to 8-cell stages normally proceed in the 4-cell stage-arrested embryos, except for a portion of the genes whose expression profiles closely parallel the stages of embryonic development when arrested in G2 and released to resume development. These parallel genes include the genes encoding intercellular adhesion molecules, whose expression is found to be positively regulated by the ERK pathway. We also show that while ERK inactivation in the 8-cell stage embryos does not lead to cell division arrest, it does cause cell division arrest when cadherin-mediated cell-cell adhesion is disrupted. These results demonstrate an essential role of ERK function in the G2/M transition and the expression of adhesion molecules during the 2-cell to 8-cell stage embryos, and suggest a loose parallelism between the gene expression programs and the developmental stages before compaction. Experiment Overall Design: We examined expression profiles of genes during early cell division stages in mouse preimplantation development. We performed the genome-wide analysis by using Affymetrix GeneChip oligonucleotide microarrays, and examined the effect of the ERK pathway inhibitor U0126 on the expression profiles. Two independent experiments were carried out. We collected embryos at six points as follows; control embryos at day 1.5 (cont. 1.5, 2-cell stage), day 2.5 (cont. 2.5, 4- to 8-cell), and day 3.5 (cont. 3.5, morula to blastocyst), and the U0126-treated embryos at day 2.5 (U2.5, 4-cell arrested), embryos released from the U0126-induced arrest at day 3.5 (U3.5, 8-cell) and at day 4.5 (U4.5, morula to blastocyst). Hybridization was carried out with the Mouse Genome 430 2.0 array following Affymetrix instructions. Hybridized arrays were scanned using an Affymetrix GeneChip Scanner. Expression analysis was performed using GeneChip Operating Software v. 1.2 (GCOS) and GeneSpring 7.3.

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PAR3-mediated coordination of hepatocyte proliferation, maturation, and architecture in liver development and regeneration

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