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.
Highlights
The in vivo function of Ppm1a in mammals remains unknown
To generate the Ppm1a targeting construct, a neomycin resistance cassette flanked by two FRT sites and a single LoxP site is inserted into the upstream of exon 2 of Ppm1a gene, and the second LoxP site was introduced into intron 3
Deletion of Ppm1a is dispensable for embryonic development and adult homeostasis; second, deletion of Ppm1a leads to delayed re-epithelialization during wound healing via decreased keratinocyte migration; third, Ppm1a can repress overactivation of Smad2 signaling, which is inhibitory for epidermal cell migration in wound healing
Summary
Results: Mice lacking Ppm1a developed normally but showed delayed re-epithelialization with retarded keratinocyte migration caused by overactivation of Smad during cutaneous wound healing. 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. 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 Smad signaling, plays a critical role in re-epithelialization during wound healing. We analyzed the wound healing phenotypes of two in vivo models of Ppm1a deficiency and demonstrated that Ppm1a promoted reepithelialization by suppressing Smad2-mediated signaling
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