PC7 and the related proteases Furin and Pace4 regulate E-cadherin function during blastocyst formation

Area of Science:

• Developmental Biology
• Cell Biology
• Molecular Biology

Background:

• Early mammalian embryonic development involves cell differentiation to form trophectoderm and inner cell mass (ICM).
• Cell polarization and adhesion, involving the Hippo signaling pathway, are critical for this lineage decision in morulae.
• The precise regulatory mechanisms governing these processes remain incompletely understood.

Purpose of the Study:

• To investigate the role of proprotein convertases (PCs), specifically PC7, Furin, and Pace4, in mammalian embryonic development.
• To elucidate how these proteases influence morula compaction, ICM formation, and cell-cell adhesion.
• To map the activity of these PCs during early embryogenesis.

Main Methods:

• Utilized genetic manipulation of PC7, Furin, and Pace4 in mouse embryos.
• Employed live imaging with a transgenic reporter substrate to track protease activity spatiotemporally.
• Applied differential inhibition using a common inhibitor to analyze protease function in distinct cellular compartments.

Main Results:

• Morula compaction and ICM formation were found to be dependent on PC7 and related PCs (Furin, Pace4).
• These proteases were shown to jointly regulate cell-cell adhesion through the processing of E-cadherin.
• Live imaging revealed distinct, partially overlapping spatiotemporal activity profiles for PC7, Furin, and Pace4 in inner and outer embryonic cells.

Conclusions:

• Proprotein convertases (PC7, Furin, Pace4) are essential regulators of early mammalian embryonic development.
• E-cadherin processing by multiple PCs represents a novel mechanism controlling cell-cell adhesion and cell fate allocation.
• Understanding PC activity is key to deciphering the molecular basis of lineage segregation in mammalian embryos.