title: Foxi3 Deficiency Compromises Hair Follicle Stem Cell Specification and Activation.
abstract: The hair follicle is an ideal system to study stem cell specification and homeostasis due to its well characterized morphogenesis and stereotypic cycles of stem cell activation upon each hair cycle to produce a new hair shaft. The adult hair follicle stem cell niche consists of two distinct populations, the bulge and the more activation-prone secondary hair germ (HG). Hair follicle stem cells are set aside during early stages of morphogenesis. This process is known to depend on the Sox9 transcription factor, but otherwise the establishment of the hair follicle stem cell niche is poorly understood. Here, we show that that mutation of Foxi3, a Forkhead family transcription factor mutated in several hairless dog breeds, compromises stem cell specification. Further, loss of Foxi3 impedes hair follicle downgrowth and progression of the hair cycle. Genome-wide profiling revealed a number of downstream effectors of Foxi3 including transcription factors with a recognized function in hair follicle stem cells such as Lhx2, Runx1, and Nfatc1, suggesting that the Foxi3 mutant phenotype results from simultaneous downregulation of several stem cell signature genes. We show that Foxi3 displays a highly dynamic expression pattern during hair morphogenesis and cycling, and identify Foxi3 as a novel secondary HG marker. Absence of Foxi3 results in poor hair regeneration upon hair plucking, and a sparse fur phenotype in unperturbed mice that exacerbates with age, caused by impaired secondary HG activation leading to progressive depletion of stem cells. Thus, Foxi3 regulates multiple aspects of hair follicle development and homeostasis. Stem Cells 2016;34:1896-1908.
authors.affiliation: Research Program in Developmental Biology, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Vera
authors.initials: V
authors.lastname: Shirokova
authors.affiliation: Research Program in Developmental Biology, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Leah C
authors.initials: LC
authors.lastname: Biggs
authors.affiliation: Research Program in Developmental Biology, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Jussila
authors.affiliation: Department of Otolaryngology - Head & Neck Surgery and Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ohyama
authors.affiliation: Program in Developmental Biology, Department of Molecular and Human Genetics and Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Andrew K
authors.initials: AK
authors.lastname: Groves
authors.affiliation: Research Program in Developmental Biology, Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
authors.forename: Marja L
authors.initials: ML
authors.lastname: Mikkola
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002451:Cell Compartmentation / Q000187:drug effects; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D004622:Embryo, Mammalian / Q000378:metabolism; D025461:Feedback, Physiological / Q000187:drug effects; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D051858:Forkhead Transcription Factors / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D018859:Hair Follicle / Q000166:cytology* / Q000254:growth & development / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009024:Morphogenesis / Q000187:drug effects / Q000235:genetics; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction; D013234:Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D051153:Wnt Proteins / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D051858:Forkhead Transcription Factors; C585346:Foxi3 protein, mouse; D051153:Wnt Proteins; D005346:Fibroblast Growth Factors
keywords: Ectodermal dysplasia; Hair follicle stem cells; Morphogenesis; Shh