title: Smad1 and 5 but not Smad8 establish stem cell quiescence which is critical to transform the premature hair follicle during morphogenesis toward the postnatal state.
abstract: Hair follicles (HFs) are regenerative miniorgans that offer a highly informative model system to study the regulatory mechanisms of hair follicle stem cells (hfSCs) homeostasis and differentiation. Bone morphogenetic protein (BMP) signaling is key in both of these processes, governing hfSCs quiescence in the bulge and differentiation of matrix progenitors. However, whether canonical or noncanonical pathways of BMP signaling are responsible for these processes remains unresolved. Here, we conditionally ablated two canonical effectors of BMP signaling, Smad1 and Smad5 during hair morphogenesis and postnatal cycling in mouse skin. Deletion of Smad1 and Smad5 (dKO) in the epidermis during morphogenesis resulted in neonatal lethality with lack of visible whiskers. Interestingly, distinct patterns of phospho-Smads (pSmads) activation were detected with pSmad8 restricted to epidermis and pSmad1 and pSmad5 exclusively activated in HFs. Engraftment of dKO skin revealed retarded hair morphogenesis and failure to differentiate into visible hair. The formation of the prebulge and bulge reservoir for quiescent hfSCs was precluded in dKO HFs which remained in prolonged anagen. Surprisingly, in postnatal telogen HFs, pSmad8 expression was no longer limited to epidermis and was also present in dKO bulge hfSCs and matrix progenitors. Although pSmad8 activity alone could not prevent dKO hfSCs precocious anagen activation, it sustained efficient postnatal differentiation and regeneration of visible hairs. Together, our data suggest a pivotal role for canonical BMP signaling demonstrating distinguished nonoverlapping function of pSmad8 with pSmad1 and pSmad5 in hfSCs regulation and hair morphogenesis but a redundant role in adult hair progenitors differentiation.
authors.affiliation: Eli and Edythe Broad CIRM Center for Regenerative Medicine and Stem Cell Research and Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA; Department of Pathology, Department of Biochemistry and Molecular Biology, USC Norris Cancer Center, University of Southern California, Los Angeles, California, USA.
authors.forename: Eve
authors.initials: E
authors.lastname: Kandyba
authors.forename: Virginia M
authors.initials: VM
authors.lastname: Hazen
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Kobielak
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Butler
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Kobielak
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D004817:Epidermis / Q000254:growth & development / Q000378:metabolism; D006197:Hair / Q000254:growth & development / Q000378:metabolism; D018859:Hair Follicle / Q000254:growth & development* / Q000378:metabolism; D051379:Mice; D009024:Morphogenesis / Q000235:genetics; D012038:Regeneration; D051898:Smad1 Protein / Q000235:genetics / Q000378:metabolism*; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism*; D051904:Smad8 Protein / Q000235:genetics / Q000378:metabolism*; D013234:Stem Cells / Q000378:metabolism
chemical_list: D051898:Smad1 Protein; C497401:Smad1 protein, mouse; D051902:Smad5 Protein; C497798:Smad5 protein, mouse; D051904:Smad8 Protein; C491621:Smad9 protein, mouse
keywords: Canonical bone morphogenetic protein signaling; Hair follicle stem cells; Progenitor cells; Smad
references.citation: Cell Stem Cell. 2009 Feb 6;4(2):155-69
references.pmid: 19200804
references.citation: Am J Pathol. 2004 Mar;164(3):1099-114
references.pmid: 14982863
references.citation: BMC Dev Biol. 2001;1:4
references.pmid: 11299042
references.citation: Cell. 2008 Jan 25;132(2):299-310
references.pmid: 18243104
references.citation: Cell Stem Cell. 2011 Sep 2;9(3):219-32
references.pmid: 21885018
references.citation: J Cell Biol. 1993 Jan;120(2):493-502
references.pmid: 8421061
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10063-8
references.pmid: 17553962
references.citation: Trends Genet. 1992 Feb;8(2):55-61
references.pmid: 1566372
references.citation: Development. 2001 Sep;128(18):3609-21
references.pmid: 11566864
references.citation: J Cell Biol. 1986 Dec;103(6 Pt 2):2593-606
references.pmid: 2432071
references.citation: Nat Cell Biol. 1999 Jul;1(3):158-64
references.pmid: 10559902
references.citation: Development. 1999 Apr;126(8):1631-42
references.pmid: 10079226
references.citation: J Histochem Cytochem. 1998 Dec;46(12):1401-10
references.pmid: 9815282
references.citation: Curr Biol. 1998 Sep 24;8(19):1058-68
references.pmid: 9768360
references.citation: Proc Natl Acad Sci U S A. 2013 Jan 22;110(4):1351-6
references.pmid: 23292934
references.citation: Genes Dev. 2005 Dec 1;19(23):2783-810
references.pmid: 16322555
references.citation: FASEB J. 2001 Oct;15(12):2205-14
references.pmid: 11641247
references.citation: Arch Oral Biol. 2012 Jun;57(6):805-13
references.pmid: 22186069
references.citation: Nature. 2008 Jan 17;451(7176):340-4
references.pmid: 18202659
references.citation: EMBO J. 2000 Dec 15;19(24):6664-74
references.pmid: 11118201
references.citation: Genes Dev. 1996 Jun 1;10(11):1382-94
references.pmid: 8647435
references.citation: J Invest Dermatol. 2002 Jan;118(1):3-10
references.pmid: 11851869
references.citation: Cell. 2004 Mar 19;116(6):769-78
references.pmid: 15035980
references.citation: Genesis. 2003 Sep;37(1):5-11
references.pmid: 14502571
references.citation: Dev Biol. 2001 Dec 1;240(1):157-67
references.pmid: 11784053
references.citation: Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8551-6
references.pmid: 10411913
references.citation: Curr Biol. 2005 Aug 9;15(15):1340-51
references.pmid: 16085486
references.citation: Development. 2004 May;131(10):2257-68
references.pmid: 15102710
references.citation: Nat Biotechnol. 2004 Apr;22(4):411-7
references.pmid: 15024388
references.citation: EMBO J. 2003 Jun 16;22(12):2992-3003
references.pmid: 12805214
references.citation: Genes Dev. 1989 Nov;3(11):1657-68
references.pmid: 2481605
references.citation: J Invest Dermatol. 2003 Apr;120(4):501-11
references.pmid: 12648211
references.citation: Science. 2006 Jun 30;312(5782):1946-9
references.pmid: 16809539
references.citation: Stem Cells. 2006 Dec;24(12):2826-39
references.pmid: 16960130
references.citation: Cell. 1990 Jun 29;61(7):1329-37
references.pmid: 2364430
references.citation: Genes Dev. 1993 Feb;7(2):204-15
references.pmid: 8436293
references.citation: J Invest Dermatol. 1998 Dec;111(6):955-62
references.pmid: 9856802
references.citation: Nature. 2007 Feb 22;445(7130):834-42
references.pmid: 17314969
references.citation: Differentiation. 2004 Dec;72(9-10):512-26
references.pmid: 15617562
references.citation: J Cell Biol. 2003 Nov 10;163(3):609-23
references.pmid: 14610062
references.citation: Genesis. 2002 Feb;32(2):76-9
references.pmid: 11857782
references.citation: Genes Dev. 2003 Sep 1;17(17):2108-22
references.pmid: 12923059
references.citation: Dev Biol. 2006 Aug 1;296(1):104-18
references.pmid: 16765933
references.citation: Cell. 2004 Sep 3;118(5):635-48
references.pmid: 15339667
references.citation: Dev Biol. 1976 Jul 1;51(1):166-71
references.pmid: 950073
references.citation: Dev Dyn. 1996 Dec;207(4):439-49
references.pmid: 8950518
references.citation: J Invest Dermatol. 2002 Feb;118(2):216-25
references.pmid: 11841536
references.citation: Exp Dermatol. 1999 Aug;8(4):367-8
references.pmid: 10439283
references.citation: Cell Stem Cell. 2008 Jul 3;3(1):33-43
references.pmid: 18593557
references.citation: Mech Dev. 1996 Jul;57(2):159-68
references.pmid: 8843393
references.citation: Cell. 2006 Oct 6;127(1):171-83
references.pmid: 17018284