In a first phase of efforts, we discovered that the Tabby mouse, which has many of the features observed in human EDA, is specifically mutated in the corresponding mouse gene. We demonstrated that the Wnt pathway directly regulates EDA transcription. In published work, we further found that provision of DNA encoding a variant of ectodysplasin (Eda-A1, the longest isoform) in embryonic Tabby mice restores hair follicles and sweat glands. By generating Tet-regulated conditional transgenic mice, we have dissected spatiotemporal actions of Eda-A1 during hair follicle development. We also have characterized eye phenotypes of Tabby mice including blindness and inflammation susceptibility, and they are also reversed by supplementation with the same Eda-A1 isoform. This study has provided the first animal model for ocular surface disease, and also further increased the interest in the possibility of manipulating the Eda pathway to combat dry eye. By large scale genome-wide expression profiling of samples from wild-type and Tabby mice ranging from embryos to adult and from hair follicles to sweat glands and primary keratinocytes, we identified numerous downstream target genes of Eda, including lymphotoxin-, Shh, Wnt10b and Dkk4 in hair follicles and Shh and FoxA1 in sweat glands. More recently, we have further focused on the function of Eda and Eda target genes identified by expression profiling in mutant mouse models. We demonstrated that target gene lymphotoxin-, an immune gene, is involved in hair shaft formation, but not hair follicle induction. We also found that Dkk4, a Wnt antagonist, discriminates an Eda-independent mechanism of secondary hair follicle formation. Notably, both pathways converge at the activation of downstream Shh. Based on these observation, we proposed that different subtypes of hair follicles are formed by variant molecular mechanisms. Conditional Shh transgenic mice and skin-specific Shh knockout mice in wild-type and Tabby backgrounds showed that Shh is required for elongation of Tabby hair shafts, but not for the induction of the primary hair follicles that are missing in Tabby mice. We have now initiated projects for skin exocrine glands, again with Tabby mice as a model system. In sweat glands, FoxA1 was strikingly affected gene in Tabby during late developmental stages and adult stage. Skin-specific FoxA1 knockout mice showed striking anhidrosis, with abundant accumulation of glycoproteins in the lumens and ducts of otherwise complete sweat glands;and we further showed that FoxA1 functions in sweat glands by promoting transcription of an anion channel protein, Best2. Best2 knockout mice also showed severe hypohidrosis/anhidrosis, revealing a FoxA1-Best2 cascade as a fundamental genetic pathway in sweat glands, regulating sweat secretion.
| 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 |
Showing the most recent 10 out of 14 publications
