title: APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
abstract: Hereditary hypotrichosis simplex is a rare autosomal dominant form of hair loss characterized by hair follicle miniaturization. Using genetic linkage analysis, we mapped a new locus for the disease to chromosome 18p11.22, and identified a mutation (Leu9Arg) in the adenomatosis polyposis down-regulated 1 (APCDD1) gene in three families. We show that APCDD1 is a membrane-bound glycoprotein that is abundantly expressed in human hair follicles, and can interact in vitro with WNT3A and LRP5-two essential components of Wnt signalling. Functional studies show that APCDD1 inhibits Wnt signalling in a cell-autonomous manner and functions upstream of beta-catenin. Moreover, APCDD1 represses activation of Wnt reporters and target genes, and inhibits the biological effects of Wnt signalling during both the generation of neurons from progenitors in the developing chick nervous system, and axis specification in Xenopus laevis embryos. The mutation Leu9Arg is located in the signal peptide of APCDD1, and perturbs its translational processing from the endoplasmic reticulum to the plasma membrane. APCDD1(L9R) probably functions in a dominant-negative manner to inhibit the stability and membrane localization of the wild-type protein. These findings describe a novel inhibitor of the Wnt signalling pathway with an essential role in human hair growth. As APCDD1 is expressed in a broad repertoire of cell types, our findings indicate that APCDD1 may regulate a diversity of biological processes controlled by Wnt signalling.
authors.affiliation: Department of Dermatology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, VC15 204A, New York, New York 10032, USA.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shimomura
authors.forename: Dritan
authors.initials: D
authors.lastname: Agalliu
authors.forename: Alin
authors.initials: A
authors.lastname: Vonica
authors.forename: Victor
authors.initials: V
authors.lastname: Luria
authors.forename: Muhammad
authors.initials: M
authors.lastname: Wajid
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baumer
authors.forename: Serena
authors.initials: S
authors.lastname: Belli
authors.forename: Lynn
authors.initials: L
authors.lastname: Petukhova
authors.forename: Albert
authors.initials: A
authors.lastname: Schinzel
authors.forename: Ali H
authors.initials: AH
authors.lastname: Brivanlou
authors.forename: Ben A
authors.initials: BA
authors.lastname: Barres
authors.forename: Angela M
authors.initials: AM
authors.lastname: Christiano
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002460:Cell Line; D049109:Cell Proliferation; D002642:Chick Embryo; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18 / Q000235:genetics; D005799:Genes, Dominant / Q000235:genetics; D017930:Genes, Reporter / Q000235:genetics; D006197:Hair / Q000254:growth & development / Q000378:metabolism; D018859:Hair Follicle / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007039:Hypotrichosis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D008565:Membrane Proteins; D051379:Mice; D050505:Mutant Proteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D017354:Point Mutation / Q000235:genetics*; D012535:Scalp; D015398:Signal Transduction; D012867:Skin; D013116:Spinal Cord / Q000166:cytology; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D029867:Xenopus Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
chemical_list: C549624:APCDD1 protein, human; C549625:Apcdd1 protein, Xenopus; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D050505:Mutant Proteins; D051153:Wnt Proteins; D029867:Xenopus Proteins; D051176:beta Catenin
references.citation: PLoS One. 2008 May 14;3(5):e2142
references.pmid: 18478089
references.citation: Curr Biol. 1994 Aug 1;4(8):676-86
references.pmid: 7953553
references.citation: Am J Hum Genet. 2007 Feb;80(2):316-28
references.pmid: 17236136
references.citation: Cell. 1998 Nov 25;95(5):605-14
references.pmid: 9845363
references.citation: Neuron. 2004 Sep 2;43(5):687-701
references.pmid: 15339650
references.citation: Cell. 1991 Oct 4;67(1):79-87
references.pmid: 1717160
references.citation: Genes Dev. 1996 Nov 1;10(21):2805-17
references.pmid: 8946920
references.citation: Nat Rev Mol Cell Biol. 2009 Mar;10(3):207-17
references.pmid: 19209183
references.citation: Neural Dev. 2007 Jul 02;2:13
references.pmid: 17605791
references.citation: Development. 2008 Jun;135(12):2161-72
references.pmid: 18480165
references.citation: Am J Hum Genet. 2008 Mar;82(3):737-43
references.pmid: 18304493
references.citation: J Dermatol Sci. 2003 Feb;31(1):43-51
references.pmid: 12615363
references.citation: Br J Dermatol. 1974 Dec;91(6):687-96
references.pmid: 4141628
references.citation: Dev Cell. 2006 Sep;11(3):325-37
references.pmid: 16950124
references.citation: Differentiation. 2006 Mar;74(2-3):129-40
references.pmid: 16533311
references.citation: Am J Hum Genet. 2000 Jun;66(6):1979-83
references.pmid: 10793007
references.citation: J Invest Dermatol. 2001 Mar;116(3):359-65
references.pmid: 11231308
references.citation: J Biol Chem. 2003 Jul 11;278(28):25600-6
references.pmid: 12724320
references.citation: Development. 2006 Apr;133(7):1205-17
references.pmid: 16527985
references.citation: Hum Mol Genet. 2005 Jun 15;14(12):1679-90
references.pmid: 15879434
references.citation: Gene. 1991 Dec 15;108(2):193-9
references.pmid: 1660837
references.citation: Nat Rev Genet. 2004 Jun;5(6):425-34
references.pmid: 15153995
references.citation: Gene Expr Patterns. 2004 Oct;4(6):755-62
references.pmid: 15465500
references.citation: Neuron. 2008 Dec 26;60(6):1039-53
references.pmid: 19109910
references.citation: Dev Biol. 2007 May 15;305(2):498-507
references.pmid: 17397822
references.citation: Nat Genet. 2008 Mar;40(3):329-34
references.pmid: 18297070
references.citation: Dev Biol. 2002 Oct 1;250(1):112-27
references.pmid: 12297100
references.citation: Genes Dev. 1996 Dec 15;10(24):3116-28
references.pmid: 8985181
references.citation: Eur J Hum Genet. 2000 Jun;8(6):443-8
references.pmid: 10878665
references.citation: Cell. 1997 Mar 21;88(6):757-66
references.pmid: 9118219
references.citation: J Invest Dermatol. 2004 Oct;123(4):613-21
references.pmid: 15373764
references.citation: Genes Dev. 1997 Sep 15;11(18):2359-70
references.pmid: 9308964
references.citation: Exp Gerontol. 2002 Aug-Sep;37(8-9):981-90
references.pmid: 12213548
references.citation: Cell. 1997 Mar 21;88(6):747-56
references.pmid: 9118218
references.citation: Development. 2002 May;129(9):2087-98
references.pmid: 11959819
references.citation: Genes Dev. 2000 May 15;14(10):1181-5
references.pmid: 10817753
references.citation: Science. 2007 Aug 10;317(5839):803-6
references.pmid: 17690294
references.citation: J Biol Chem. 1996 Jul 19;271(29):17445-52
references.pmid: 8663413
references.citation: Cancer Res. 2002 Oct 15;62(20):5651-6
references.pmid: 12384519
references.citation: Cell. 2000 May 12;101(4):435-45
references.pmid: 10830170
references.citation: Development. 2008 Nov;135(22):3687-96
references.pmid: 18927156
references.citation: Neural Dev. 2009 Jan 05;4:2
references.pmid: 19123929
references.citation: J Cell Sci. 2003 Jul 1;116(Pt 13):2627-34
references.pmid: 12775774
references.citation: J Cell Mol Med. 2008 Apr;12(2):391-408
references.pmid: 18088386
references.citation: Acta Derm Venereol. 1991;71(4):349-51
references.pmid: 1681656
references.citation: Histochemistry. 1993 Dec;100(6):431-40
references.pmid: 7512949