APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
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.
Shimomura
Yutaka
Y
Department of Dermatology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, VC15 204A, New York, New York 10032, USA.
Agalliu
Dritan
D
Vonica
Alin
A
Luria
Victor
V
Wajid
Muhammad
M
Baumer
Alessandra
A
Belli
Serena
S
Petukhova
Lynn
L
Schinzel
Albert
A
Brivanlou
Ali H
AH
Barres
Ben A
BA
Christiano
Angela M
AM
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
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
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