X-linked anhidrotic ectodermal dysplasia (EDA) is the most frequently occurring of more than 175 ectodermal dysplasias affecting one or more skin appendages. The gene that is mutated to cause this disorder encodes a protein, which we have named ectodysplasin-A, has a single transmembrane region with collagenous and TNF-ligand segments in a long extracelliular carboxyterminal tail. Because individuals with EDA have sparse hair, rudimentary teeth, and few sweat glands, the gene is likely involved at an early point in development. We demonstrated that the Tabby mouse, which has many of the features observed in human EDA, is specifically mutated in the corresponding mouse gene. We found that provision of DNA encoding a variant of ectodysplasin in embryonic mice rstores hair follicles and sweat glands. We also have characterized eye phenotypes of Tabby mice including blindness and inflammation susceptibility, and they are also reversed by supplementation with the same isoform. In additional studies to look at the final phases of hair follicle development, we have also studied the human disease Cartilage Hair Hypoplasia in a mouse model. These studies should facilitate attempts to maintain or reform hair follicles. We have continued to progress in the EDA project during the last year. By generating a conditional transgenic mouse model, we revealed spatiotemporal actions of Eda-a1 during hair follicle development. For example, we found that Eda-a1 is needed only for induction and initial progression stages, but not for late differentiation stage of hair follicles. We also showed that Eda-a1 was able to partially restore secondary hair including zigzag subtype in Tabby mice. (J. Inf. Dis., 2009) We found that Dkk4, a soluble Wnt antagonist, discriminates an Eda-independent mechanism of secondary hair follicle formation. It was a long-standing puzzle that Tabby mice lack primary hair, but produce large numbers of secondary hair. We revealed that while Eda controls primary hair follicle development, Dkk4 exclusively regulates secondary hair follicle formation. Notably, both pathways converge at the activation of downstream Shh (manuscript in submission) Finally, we completed a genome-wide expression profiling for sweat gland development. We found that Shh and Foxa1 are likely key effectors for sweat gland development under Eda regulation, and we are currently generating conditional mouse models to understand their functions. (Hum. Mol. Genet., 2009)

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAG000643-12
Application #
7963994
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2009
Total Cost
$383,920
Indirect Cost
Name
National Institute on Aging
Department
Type
DUNS #
City
State
Country
Zip Code
Cui, Chang-Yi; Noh, Ji Heon; Michel, Marc et al. (2018) STIM1, but not STIM2, Is the Calcium Sensor Critical for Sweat Secretion. J Invest Dermatol 138:704-707
Cui, C-Y; Schlessinger, D (2017) Neuropeptide PACAP promotes sweat secretion. Br J Dermatol 176:295-296
Cui, Chang-Yi; Ishii, Ryuga; Campbell, Dean P et al. (2017) Foxc1 Ablated Mice Are Anhidrotic and Recapitulate Features of Human Miliaria Sweat Retention Disorder. J Invest Dermatol 137:38-45
Cui, Chang-Yi; Piao, Yulan; Campbell, Dean P et al. (2017) miRNAs Are Required for Postinduction Stage Sweat Gland Development. J Invest Dermatol 137:1571-1574
Sima, Jian; Piao, Yulan; Chen, Yaohui et al. (2016) Molecular dynamics of Dkk4 modulates Wnt action and regulates meibomian gland development. Development 143:4723-4735
Cui, Chang-Yi; Sima, Jian; Yin, Mingzhu et al. (2016) Identification of potassium and chloride channels in eccrine sweat glands. J Dermatol Sci 81:129-31
Cui, Chang-Yi; Schlessinger, David (2015) Eccrine sweat gland development and sweat secretion. Exp Dermatol 24:644-50
Cui, Chang-Yi; Yin, Mingzhu; Sima, Jian et al. (2014) Involvement of Wnt, Eda and Shh at defined stages of sweat gland development. Development 141:3752-60
Cui, Chang-Yi; Klar, Joakim; Georgii-Heming, Patrik et al. (2013) Frizzled6 deficiency disrupts the differentiation process of nail development. J Invest Dermatol 133:1990-7
Cui, Chang-Yi; Kunisada, Makoto; Childress, Victoria et al. (2011) Shh is required for Tabby hair follicle development. Cell Cycle 10:3379-86

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