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Delayed re-epithelialization in Ppm1a gene-deficient mice is mediated by enhanced activation of Smad2
Xue Yang1, Yan Teng2, Ning Hou2
1State Key Laboratory of Proteomics, Genetic Laboratory of Development and Disease, Institute of Biotechnology, Beijing 100071, P.R. China; Model Organism Division, E-institutes of Shanghai Universities, Shanghai JiaoTong University, Shanghai 200025, P.R. China.
Abstract:
Protein phosphatase magnesium-dependent 1A (PPM1A), a protein serine/threonine phosphatase, controls several signal pathways through cleavage of phosphate from its substrates. However, the in vivo function of Ppm1a in mammals remains unknown. Here we reported that mice lacking Ppm1a developed normally but were impaired in re-epithelialization process during cutaneous wound healing. Specifically, complete or keratinocyte-specific deletion of Ppm1a led to delayed re-epithelialization with reduced keratinocyte migration upon wounding. We showed that this effect was the result of an increase in Smad2/3 phosphorylation in keratinocytes. Keratinocyte-specific Smad2 deficient mice displayed accelerated re-epithelialization with enhanced keratinocyte migration. Importantly, Smad2 and Ppm1a double mutant mice also exhibited accelerated re-epithelialization, demonstrating that the effect of Ppm1a on promoting re-epithelialization is mediated by Smad2 signaling. Furthermore, the decreased expression of specific integrins and matrix metalloproteinases (MMPs) may contribute to the retarded re-epithelialization in Ppm1a mutant mice. These data indicate that Ppm1a, through suppressing Smad2 signaling, plays a critical role in re-epithelialization during wound healing.
Insights
Protein phosphatase magnesium-dependent 1A (PPM1A) is crucial for skin wound healing. PPM1A deficiency impairs keratinocyte migration and delays re-epithelialization by increasing Smad2/3 phosphorylation.
Area of Science:
- Molecular Biology
- Cell Biology
- Dermatology
Background:
- Protein phosphatase magnesium-dependent 1A (PPM1A) regulates cellular signaling by dephosphorylating substrates.
- The in vivo function of PPM1A in mammalian skin repair remains largely uncharacterized.
Purpose of the Study:
- To investigate the role of PPM1A in mammalian cutaneous wound healing.
- To elucidate the molecular mechanisms underlying PPM1A's function in re-epithelialization.
Main Methods:
- Generation and analysis of Ppm1a knockout and keratinocyte-specific knockout mice.
- Assessment of keratinocyte migration and re-epithelialization in wound models.
- Analysis of Smad2/3 phosphorylation, integrin, and matrix metalloproteinase (MMP) expression.
Main Results:
- Mice lacking Ppm1a exhibited delayed re-epithelialization and reduced keratinocyte migration.
- Ppm1a deficiency led to increased Smad2/3 phosphorylation in keratinocytes.
- Smad2 deficiency accelerated re-epithelialization, and double mutant mice showed similar acceleration, confirming Smad2 mediation.
- Decreased expression of specific integrins and MMPs was observed in Ppm1a mutant mice.
Conclusions:
- PPM1A plays a critical role in promoting re-epithelialization during cutaneous wound healing.
- PPM1A functions by suppressing Smad2 signaling, thereby enhancing keratinocyte migration.
- These findings highlight PPM1A as a potential therapeutic target for improving wound repair.
