Two Distinct Mechanisms of PP2A Regulation by Methylesterase PME-1 Are Both Essential for Mouse Development

Area of Science:

• Biochemistry
• Molecular Biology
• Developmental Biology

Background:

• Protein methylesterase-1 (PME-1) regulates protein phosphatases 2A (PP2A) and PP4.
• PME-1 dysregulation is linked to neurodegenerative diseases and cancer.
• PME-1 possesses both methylesterase and PP2A inhibitory activities, with unclear in vivo roles.

Purpose of the Study:

• To investigate the distinct in vivo functions of PME-1's methylesterase and PP2A inhibitory activities.
• To generate and characterize PME-1 knock-in mouse models with specific loss-of-function mutations.

Main Methods:

• Generation of PME-1 S156A (methylesterase-deficient) and M335D (PP2A inhibitory-deficient) knock-in mice.
• Phenotypic analysis including histology, gene expression, and cell-based assays.
• Assessment of developmental outcomes, apoptosis, inflammation, and metabolic parameters.

Main Results:

• S156A mutation caused systemic apoptosis, brain atrophy, cerebellar abnormalities, increased inflammation, and altered mitochondrial function.
• M335D mutation led to neonatal death with olfactory epithelium apoptosis and loss of olfaction.
• Both mutations exhibited distinct developmental phenotypes compared to PME-1 null mice.

Conclusions:

• PME-1 regulates mouse development through distinct mechanisms involving its methylesterase and PP2A inhibitory functions.
• Loss of methylesterase activity impacts brain development and cellular metabolism.
• Loss of PP2A inhibitory activity affects olfactory development and survival.