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APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
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APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
Nature. 2010 Apr 15;464(7291):1043-7.
APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
Shimomura Y, Agalliu D, Vonica A, Luria V, Wajid M, Baumer A, Belli S, Petukhova L, Schinzel A, Brivanlou AH, Barres BA, Christiano AM.
Department of Dermatology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, VC15 204A, New York, New York 10032, USA.
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.
APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
Shimomura Y, Agalliu D, Vonica A, Luria V, Wajid M, Baumer A, Belli S, Petukhova L, Schinzel A, Brivanlou AH, Barres BA, Christiano AM.
Department of Dermatology, Columbia University, College of Physicians and Surgeons, 630 West 168th Street, VC15 204A, New York, New York 10032, USA.
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.
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Re: APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
This is really interesting CS!
Think there is any possibility that sulforaphane could modulate the gene expression that causes this? Turn the switch on/off?
Think there is any possibility that sulforaphane could modulate the gene expression that causes this? Turn the switch on/off?
Icanbeatthis- Posts : 108
Join date : 2008-09-22
Re: APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
Icanbeatthis - I agree, I think this is very interesting, and sulforaphane may very likely play a role in this. The first study I listed below shows this genes role (I prefer to say reaction) to colon cancer.
Then in the second link below, there is the positive mechanism that sulforaphane has on the same cell line. Given sulforaphanes roles in other areas, this at least shows potential that sulforaphane may intervene in this process.
However, as it shows in the 2nd link sulforaphane does not affect the Wnt signaling pathway. This doesn't mean that it won't help hair, as it may overide other mechanisms, but more research is probably needed.
http://cancerres.aacrjournals.org/cgi/content/full/62/20/5651
http://carcin.oxfordjournals.org/cgi/content/full/27/10/2038
Then in the second link below, there is the positive mechanism that sulforaphane has on the same cell line. Given sulforaphanes roles in other areas, this at least shows potential that sulforaphane may intervene in this process.
However, as it shows in the 2nd link sulforaphane does not affect the Wnt signaling pathway. This doesn't mean that it won't help hair, as it may overide other mechanisms, but more research is probably needed.
http://cancerres.aacrjournals.org/cgi/content/full/62/20/5651
http://carcin.oxfordjournals.org/cgi/content/full/27/10/2038
_________________
My regimen
http://www.immortalhair.org/mpb-regimen
Now available for consultation (hair and/or health)
http://www.immortalhair.org/health-consultation
Re: APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
This caught my eye recently, would one assume that APCDD1 (hypotrichosis simplex) mediated hairloss would look much different than other forms?
Found this, not sure if it's any use.
Should I take from this that things like bad circulation / oxygenation of cells would instigate these genes which inhibit WNT signaling?
Found this, not sure if it's any use.
Hypotrichosis simplex is a group of nonsyndromic human alopecias. We mapped an autosomal recessive form of this disorder to chromosome 13q14.11–13q21.33, and identified homozygous truncating mutations in P2RY5, which encodes an orphan G protein–coupled receptor. Furthermore, we identified oleoyl-L-alpha-lysophosphatidic acid (LPA), a bioactive lipid, as a ligand for P2Y5 in reporter gene and radioligand binding experiments. Homology and studies of signaling transduction pathways suggest that P2Y5 is a member of a subgroup of LPA receptors, which also includes LPA4 and LPA5. Our study is the first to implicate a G protein–coupled receptor as essential for and specific to the maintenance of human hair growth. This finding may provide opportunities for new therapeutic approaches to the treatment of hair loss in humans.
Hypotrichosis simplex (HS) is a group of isolated alopecias that can be inherited as an autosomal-dominant or an autosomal-recessive trait. Hair loss usually begins in early childhood, and is diffuse and progressive. Mutations in LIPH, which encodes lipase member H, have recently been shown to cause an autosomal-recessive form of HS. Here we describe an Austrian HS patient who was found to be carrying compound heterozygous mutations in the LIPH gene: a 7-bp frameshift duplication (c.403_409dup; p.Gln137HisfsX1) and a recently reported 30-amino acid in-frame duplication (c.280_369dup; p.Gly94_Lys123dup). To examine the impact of LIPH mutations on lipid metabolism, we established an in vitro assay to measure the action of this phospholipase in a cell-based system. Both the 7-bp duplication frameshift mutation and all known in-frame mutations were observed to reduce the in vitro activity of the lipase in response to the addition of phosphatidic acid, the substrate of lipase H. The reduced production of lysophosphatidic acid (LPA) led to a reduced response of cells expressing the human G-protein-coupled receptor p2y5 (p2y5) receptor. Our study increases the spectrum of known LIPH mutations and provides biochemical evidence for the important role of lipase H and its product LPA in human hair growth.
Hypoxia enhances LPA-induced HIF-1alpha and VEGF expression: Their inhibition by resveratrol - Cancer Lett. 2007 Oct 3 - "Lysophosphatidic acid (LPA) is a bioactive phospholipid that is involved in various cellular events, including tumor invasion and metastasis ... Collectively, these results show that LPA under hypoxic condition enhances cell migration through the sequential induction of HIF-1alpha and VEGF, and that this enhancement is efficiently blocked by resveratrol"
Should I take from this that things like bad circulation / oxygenation of cells would instigate these genes which inhibit WNT signaling?
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Re: APCDD1 is a novel Wnt inhibitor mutated in hereditary hypotrichosis simplex.
I can't pick any conclusion out of all of this data, I'm hoping you can Caustic.
beta-catenin is the major effector of the canonical Wnt signaling pathway. Mutations in components of the pathway that stabilize beta-catenin result in augmented gene transcription and play a major role in many human cancers. We employed microarrays to identify transcriptional targets of deregulated beta-catenin in a human epithelial cell line (293) engineered to produce mutant beta-catenin and in ovarian endometrioid adenocarcinomas characterized with respect to mutations affecting the Wnt/beta-catenin pathway. Two genes strongly induced in both systems—FGF20 and DKK1—were studied in detail. Elevated levels of FGF20 RNA were also observed in adenomas from mice carrying the ApcMinallele. Both XFGF20 and Xdkk-1 are expressed early in Xenopus embryogenesis under the control of the Wnt signaling pathway. Furthermore, FGF20 and DKK1 appear to be direct targets for beta-catenin/TCF transcriptional regulation via LEF/TCF-binding sites. Finally, by using small inhibitory RNAs specific for FGF20, we show that continued expression of FGF20 is necessary for maintenance of the anchorage-independent growth state in RK3E cells transformed by beta-catenin, implying that FGF-20 may be a critical element in oncogenesis induced by the Wnt signaling pathway.
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