Di-Poï Nicolas, Ng Chuan Young, Tan Nguan Soon, Yang Zhongzhou, Hemmings Brian A, Desvergne Béatrice, Michalik Liliane, Wahli Walter
Center for Integrative Genomics, Biology Building, University of Lausanne, CH-1015 Lausanne, Switzerland.
Mol Cell Biol. 2005 Mar;25(5):1696-712. doi: 10.1128/MCB.25.5.1696-1712.2005.
Hair follicle morphogenesis depends on a delicate balance between cell proliferation and apoptosis, which involves epithelium-mesenchyme interactions. We show that peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) and Akt1 are highly expressed in follicular keratinocytes throughout hair follicle development. Interestingly, PPARbeta/delta- and Akt1-deficient mice exhibit similar retardation of postnatal hair follicle morphogenesis, particularly at the hair peg stage, revealing a new important function for both factors in the growth of early hair follicles. We demonstrate that a time-regulated activation of the PPARbeta/delta protein in follicular keratinocytes involves the up-regulation of the cyclooxygenase 2 enzyme by a mesenchymal paracrine factor, the hepatocyte growth factor. Subsequent PPARbeta/delta-mediated temporal activation of the antiapoptotic Akt1 pathway in vivo protects keratinocytes from hair pegs against apoptosis, which is required for normal hair follicle development. Together, these results demonstrate that epithelium-mesenchyme interactions in the skin regulate the activity of PPARbeta/delta during hair follicle development via the control of ligand production and provide important new insights into the molecular biology of hair growth.
毛囊形态发生取决于细胞增殖与凋亡之间的微妙平衡，这涉及上皮-间充质相互作用。我们发现，在毛囊发育的整个过程中，过氧化物酶体增殖物激活受体β/δ（PPARβ/δ）和Akt1在毛囊角质形成细胞中高度表达。有趣的是，PPARβ/δ和Akt1基因敲除小鼠在出生后毛囊形态发生方面表现出类似的迟缓，尤其是在毛钉期，这揭示了这两种因子在早期毛囊生长中的新的重要功能。我们证明，毛囊角质形成细胞中PPARβ/δ蛋白的时间调控激活涉及间充质旁分泌因子肝细胞生长因子对环氧合酶2的上调。随后，PPARβ/δ在体内介导的抗凋亡Akt1途径的时间激活保护毛钉中的角质形成细胞免于凋亡，这是正常毛囊发育所必需的。总之，这些结果表明，皮肤中的上皮-间充质相互作用通过控制配体产生来调节毛囊发育过程中PPARβ/δ的活性，并为毛发生长的分子生物学提供了重要的新见解。
