title: Cutaneous retinoic acid levels determine hair follicle development and downgrowth.
abstract: Retinoic acid (RA) is essential during embryogenesis and for tissue homeostasis, whereas excess RA is well known as a teratogen. In humans, excess RA is associated with hair loss. In the present study, we demonstrate that specific levels of RA, regulated by Cyp26b1, one of the RA-degrading enzymes, are required for hair follicle (hf) morphogenesis. Mice with embryonic ablation of Cyp26b1 (Cyp26b1(-/-)) have excessive endogenous RA, resulting in arrest of hf growth at the hair germ stage. The altered hf development is rescued by grafting the mutant skin on immunodeficient mice. Our results show that normalization of RA levels is associated with reinitiation of hf development. Conditional deficiency of Cyp26b1 in the dermis (En1Cre;Cyp26b1f/-) results in decreased hair follicle density and specific effect on hair type, indicating that RA levels also influence regulators of hair bending. Our results support the model of RA-dependent dermal signals regulating hf downgrowth and bending. To elucidate target gene pathways of RA, we performed microarray and RNA-Seq profiling of genes differentially expressed in Cyp26b1(-/-) skin and En1Cre;Cyp26b1f/- tissues. We show specific effects on the Wnt-catenin pathway and on members of the Runx, Fox, and Sox transcription factor families, indicating that RA modulates pathways and factors implicated in hf downgrowth and bending. Our results establish that proper RA distribution is essential for morphogenesis, development, and differentiation of hfs.
authors.affiliation: Developmental Skin Biology Section, NIAMS, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Okano
authors.forename: Clara
authors.initials: C
authors.lastname: Levy
authors.forename: Ulrike
authors.initials: U
authors.lastname: Lichti
authors.forename: Hong-Wei
authors.initials: HW
authors.lastname: Sun
authors.forename: Stuart H
authors.initials: SH
authors.lastname: Yuspa
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Sakai
authors.forename: Maria I
authors.initials: MI
authors.lastname: Morasso
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis* / Q000235:genetics; D020405:Dermis / Q000166:cytology / Q000378:metabolism*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D018859:Hair Follicle / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D007641:Keratolytic Agents / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D000072516:Retinoic Acid 4-Hydroxylase; D016038:Skin Transplantation; D014184:Transplantation, Homologous; D014212:Tretinoin / Q000494:pharmacology*; D060449:Wnt Signaling Pathway / Q000187:drug effects*
chemical_list: D007641:Keratolytic Agents; D014212:Tretinoin; D003577:Cytochrome P-450 Enzyme System; C000607079:CYP26B1 protein, human; C000607081:Cyp26b1 protein, mouse; D000072516:Retinoic Acid 4-Hydroxylase