Mammalian CDC14 phosphatases control exit from stemness in pluripotent cells

Area of Science:

• Cell Biology
• Developmental Biology
• Molecular Biology

Background:

• Stemness maintenance is regulated by cyclin-dependent kinases (CDKs) through protein phosphorylation.
• The reversal of this process during differentiation is not well understood.
• The function of CDC14 phosphatases in mammalian development remains largely unknown.

Purpose of the Study:

• To investigate the role of CDC14 phosphatases in the exit from stemness and neural differentiation.
• To elucidate the molecular mechanisms by which CDC14 controls stem cell fate.
• To establish the relationship between cell cycle regulation and stem cell self-renewal.

Main Methods:

• Utilized knockout mouse models lacking CDC14A and CDC14B.
• Employed embryonic stem cells (ESCs) for neural differentiation studies.
• Performed multiomic single-cell analysis of transcription and chromatin accessibility.
• Investigated protein dephosphorylation and degradation pathways.

Main Results:

• Loss of CDC14A and CDC14B impairs neural development and ESC neural differentiation.
• CDC14 directly dephosphorylates and triggers proteasome-dependent degradation of UTF1 during stemness exit.
• Elevated UTF1 levels in CDC14-deficient cells inhibit the activation of differentiation-specific genes.
• CDC14 phosphatases are not essential for mitotic exit, suggesting a specific role in stemness control.

Conclusions:

• CDC14 phosphatases are critical regulators of stemness exit and neural differentiation.
• The CDK-CDC14 axis acts as a molecular switch linking cell cycle regulation to self-renewal.
• CDC14-mediated degradation of UTF1 is a key step in initiating differentiation.