TY - JOUR
T1 - Frizzled6 deficiency disrupts the differentiation process of nail development
AU - Cui, Chang Yi
AU - Klar, Joakim
AU - Georgii-Heming, Patrik
AU - Fröjmark, Anne Sophie
AU - Baig, Shahid M.
AU - Schlessinger, David
AU - Dahl, Niklas
N1 - Funding Information:
We thank Yulan Piao for help for expression profiling and Alexei Sharov for statistical analysis. This work was supported in part by the Intramural Research Program of the NIH, National Institute on Aging, the Swedish Research Council (grant numbers K2010-66X-10829-17-3 and 621-2009-4629), Uppsala University, and Science for Life laboratory. JK is supported by the Swedish Society for Medical Research.
PY - 2013/8
Y1 - 2013/8
N2 - Nails protect the soft tissue of the tips of digits. The molecular mechanism of nail (and claw) development is largely unknown, but we have recently identified a Wnt receptor gene, Frizzled6 (Fzd6), that is mutated in a human autosomal-recessive nail dysplasia. To investigate the action of Fzd6 in claw development at the molecular level, we compared gene expression profiles of digit tips of wild-type and Fzd6-/- mice, and showed that Fzd6 regulates the transcription of a striking number of epidermal differentiation-related genes. Sixty-three genes encoding keratins (Krts), keratin-associated proteins, and transglutaminases (Tgms) and their substrates were significantly downregulated in the knockout mice. Among them, four hard Krts, Krt86, Krt81, Krt34, and Krt31; two epithelial Krts, Krt6a and Krt6b; and Tgm 1 were already known to be involved in nail abnormalities when dysregulated. Immunohistochemical studies revealed decreased expression of Krt86, Krt6b, and involucrin in the epidermal portion of the claw field in the knockout embryos. We further showed that Dkk4, a Wnt antagonist, was significantly downregulated in Fzd6-/- mice along with Wnt, Bmp, and Hh family genes; and Dkk4 transgenic mice showed a subtly but appreciably modified claw phenotype. Thus, Fzd6-mediated Wnt signaling likely regulates the overall differentiation process of nail/claw formation.
AB - Nails protect the soft tissue of the tips of digits. The molecular mechanism of nail (and claw) development is largely unknown, but we have recently identified a Wnt receptor gene, Frizzled6 (Fzd6), that is mutated in a human autosomal-recessive nail dysplasia. To investigate the action of Fzd6 in claw development at the molecular level, we compared gene expression profiles of digit tips of wild-type and Fzd6-/- mice, and showed that Fzd6 regulates the transcription of a striking number of epidermal differentiation-related genes. Sixty-three genes encoding keratins (Krts), keratin-associated proteins, and transglutaminases (Tgms) and their substrates were significantly downregulated in the knockout mice. Among them, four hard Krts, Krt86, Krt81, Krt34, and Krt31; two epithelial Krts, Krt6a and Krt6b; and Tgm 1 were already known to be involved in nail abnormalities when dysregulated. Immunohistochemical studies revealed decreased expression of Krt86, Krt6b, and involucrin in the epidermal portion of the claw field in the knockout embryos. We further showed that Dkk4, a Wnt antagonist, was significantly downregulated in Fzd6-/- mice along with Wnt, Bmp, and Hh family genes; and Dkk4 transgenic mice showed a subtly but appreciably modified claw phenotype. Thus, Fzd6-mediated Wnt signaling likely regulates the overall differentiation process of nail/claw formation.
UR - http://www.scopus.com/inward/record.url?scp=84880327849&partnerID=8YFLogxK
U2 - 10.1038/jid.2013.84
DO - 10.1038/jid.2013.84
M3 - Article
AN - SCOPUS:84880327849
SN - 0022-202X
VL - 133
SP - 1990
EP - 1997
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 8
ER -