Sphingosine-1-phosphate Phosphatase 1 Regulates Keratinocyte Differentiation and Epidermal Homeostasis

Sphingosine 1-phosphate (S1P) is a bioactive lipid whose levels are tightly regulated by its synthesis and degradation. Intracellularly, S1P is dephosphorylated by the actions of two S1P-specific phosphatases, sphingosine-1-phosphate phosphatases 1 and 2. To identify the physiological functions of S1P phosphatase 1, we have studied mice with its gene, Sgpp1 , deleted. Sgpp1 −/− mice appeared normal at birth, but during the 1st week of life they exhibited stunted growth and suffered desquamation, with most dying before weaning. Both Sgpp1 −/− pups and surviving adults exhibited multiple epidermal abnormalities. Interestingly, the epidermal permeability barrier developed normally during embryogenesis in Sgpp1 −/− mice. Keratinocytes isolated from the skin of Sgpp1 −/− pups had increased intracellular S1P levels and displayed a gene expression profile that indicated overexpression of genes associated with keratinocyte differentiation. The results reveal S1P metabolism as a regulator of keratinocyte differentiation and epidermal homeostasis. Background: Sphingosine-1-phosphate phosphatase 1, encoded by Sgpp1 , dephosphorylates the signaling lysophospholipid, S1P; however, its in vivo functions are not well understood. Results: Deletion of Sgpp1 causes epidermal defects with intrinsic keratinocyte abnormalities. Conclusion: Sgpp1 deficiency in keratinocytes causes S1P elevation and accelerates their differentiation. Significance: Intracellular S1P metabolism regulates keratinocyte differentiation and epidermal homeostasis.