The pathways that regulate stratified epidermis differentiation and the formation of a functional skin barrier have been a central topic of investigation in epidermal biology. Transcription is one of the most important regulatory mechanisms controlling the stepwise program of epidermal differentiation. Our research efforts have focused on characterizing the gene regulatory networks and signaling pathways linked to human diseases, such as ectodermal dysplasias and skin inflammatory disorders.
Ectodermal Dysplasias and Ectodermal Appendage Development
Ectodermal dysplasias are a group of heritable pathological disorders that results from anomalies in epithelial/mesenchymal-derived appendage formation. The DLX3 homeobox transcriptional regulator is among the factors for which mutations have been directly linked with ectodermal dysplasias. The importance of DLX3 in the patterning and development of ectodermal structures is corroborated by the effects of Dlx3 mutations in patients with autosomal dominant Tricho-Dento-Osseous (TDO) syndrome. We have demonstrated the crucial role of DLX3 in epidermal development and tooth and hair formation through direct regulation of specific sets of keratins.
Our recent work has shown that keratins are expressed in tooth and are essential organic components of the mineralized tooth enamel. Using genetic and intraoral examination data from human patients, we identified several missense polymorphisms in keratins that lead to a higher risk for dental caries. Linear regression analysis shows that missense polymorphisms in these keratin genes significantly increase susceptibility to caries in a dentition-specific (primary vs permanent) manner.
Epidermal Differentiation, Skin Barrier Formation and Inflammatory disorders
Epidermal homeostasis results from a coordinated control of keratinocyte cell cycle and differentiation with an alteration of this balance leading to cancer. Using various animal models, we have demonstrated the central role of the DLX3 transcriptional regulator during epidermal differentiation. Through a combination of transcriptomic and bioinformatic analyses we have identified a DLX3-dependent network that regulates cell cycle and the activated ERK- and PKCα-dependent signaling pathways that are crucial to maintain cutaneous homeostasis. Our studies also provide a novel understanding of the signaling networks regulating squamous tumorigenesis.
The epidermal conditional deletion of DLX3 leads to disruption of the skin barrier formation and is linked to epidermal hyperplasia with hyperkeratosis and dermal leukocyte recruitment. The development of an inflammatory response is characterized by the accumulation of IL-17-producing T cells.
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Bhattacharya, S., Kim, J.-C., Ogawa, Y., Nakato, G., Kellett, M., Nagle, V., Brooks, S., Udey, M. and Morasso, M.I. DLX3-dependent STAT3 signaling in keratinocytes regulates skin immune homeostasis. J Invest Dermatol. 2017 Dec 12. pii: S0022-202X(17)33272-4. doi: 10.1016/j.jid.2017.11.033. [Epub ahead of print]
Duverger, O., Carlson, J., Karacz, C., Schwartz, M., Cross, M., Marazita, M., Shaffer, J. and Morasso, M.I. Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay. PLoS Genet. 2018 Jan 22;14(1):e1007168. doi: 10.1371/journal.pgen.1007168. [Epub ahead of print]
Bhattacharya, S., Duverger, O., Brooks, S. and Morasso, M.I. Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis. Exp Dermatol. 2018 Jan 29. doi: 10.1111/exd.13503. [Epub ahead of print]
Bartolome-Iglesias, R. and Morasso, M.I. Policing tumorigenesis within the skin: good ousts bad. Cell Stem Cell. 2017 Oct 5;21(4):419-420. doi: 10.1016/j.stem.2017.08.019.
Palazzo, E., Kellett, M., Cataisson, C., Bible, P., Bhattacharya, S., Sun, H.-W., Gormley, A., Yuspa, S. and Morasso, M.I. A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation. Cell Death Differ. 2017 Apr;24(4):717-730. doi: 10.1038/cdd.2017.5. Epub 2017 Feb 10.
Duverger, O., Ohara, T., Bible, P. Zah, A. and Morasso, M.I. DLX3-dependent regulation of ion transporters and carbonic anhydrases is crucial for enamel mineralization. J Bone Miner Res. 2017 Mar;32(3):641-653. doi: 10.1002/jbmr.3022. Epub 2017 Feb 23.
Peled, A., Sarig, O., Samuelov, L., Bertolini, M., Ziv, L., Weissglas-Volkov, D., Eskin-Schwartz, M., Adase, C.A., Malchin, N., Bochner, R., Fainberg, G., Goldberg, I., Sugawara, K., Baniel, A., Tsuruta, D., Luxemburg, C., Adir, N., Duverger, O., Morasso, M., Shalev, S., Gallo, R., Shomron N., Paus, R., Sprecher, E. Mutations in TSPEAR, encoding a regulator of Notch signaling, affect tooth and hair follicle morphogenesis. PLoS Genet. 2016 Oct 13;12(10):e1006369. doi: 10.1371/journal.pgen.1006369. eCollection 2016 Oct.
Palazzo, E., Kellett, M., Cataisson, C., Gormley, A., Bible, P., Pietroni, V., Radoja, N., Blumenberg, M., Hwang, J., Yuspa, S. and Morasso, M.I. The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth. Oncogene. 2016 Jun 16;35(24):3114-24. doi: 10.1038/onc.2015.380. Epub 2015 Nov 2.
Duverger, O., Beniash, E. and Morasso, M.I. Keratins as components of the enamel organic matrix. Matrix Biol. 2016 May-Jul;52-54:260-265. doi: 10.1016/j.matbio.2015.12.007. Epub 2015 Dec 17. Review.
Lessard, J., Kalinin, O., Bible, P. and Morasso, M.I. Calm4 is dispensible for epidermal barrier formation and wound healing in mice. Exp Dermatol. 2015 Jan;24(1):55-7. doi: 10.1111/exd.12568. Epub 2014 Nov 20.
Duverger, O., Ohara, T., Shaffer, J., Donahue, D., Zerfas, P., Dullnig, A., Crecelius, C., Beniash, E., Marazita, M. and Morasso, M.I. Hair keratin mutations in tooth enamel increase dental decay risk. J Clin Invest. 2014 Dec;124(12):5219-24. doi: 10.1172/JCI78272. Epub 2014 Oct 27.
Keratins are proteins that are key structural components of hair, nails, and the skin’s outer layer.