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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Scientific Publications



SOX2 Epidermal Overexpression Promotes Cutaneous Wound Healing via Activation of EGFR/MEK/ERK Signaling Mediated by EGFR Ligands.

Uchiyama A, Nayak S, Graf R, Cross M, Hasneen K, Gutkind JS, Brooks SR, Morasso MI
The Journal of investigative dermatology.
2019 Aug;
doi: 10.1016/j.jid.2019.02.004
PMID: 30772301

Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway.

Wright JT, Fete M, Schneider H, Zinser M, Koster MI, Clarke AJ, Hadj-Rabia S, Tadini G, Pagnan N, Visinoni AF, Bergendal B, Abbott B, Fete T, Stanford C, Butcher C, D'Souza RN, Sybert VP, Morasso MI
American journal of medical genetics. Part A.
2019 Mar;
doi: 10.1002/ajmg.a.61045
PMID: 30703280

Transcriptional signature primes human oral mucosa for rapid wound healing.

Iglesias-Bartolome R, Uchiyama A, Molinolo AA, Abusleme L, Brooks SR, Callejas-Valera JL, Edwards D, Doci C, Asselin-Labat ML, Onaitis MW, Moutsopoulos NM, Gutkind JS, Morasso MI
Science translational medicine.
2018 Jul 25;
pii: eaap8798. doi: 10.1126/scitranslmed.aap8798
PMID: 30045979

Enamel Anomalies in a Pachyonychia Congenita Patient with a Mutation in KRT16.

Duverger O, Cross MA, Smith FJD, Morasso MI
The Journal of investigative dermatology.
2019 Jan;
doi: 10.1016/j.jid.2018.07.005
PMID: 30009827

A data mining paradigm for identifying key factors in biological processes using gene expression data.

Li J, Zheng L, Uchiyama A, Bin L, Mauro TM, Elias PM, Pawelczyk T, Sakowicz-Burkiewicz M, Trzeciak M, Leung DYM, Morasso MI, Yu P
Scientific reports.
2018 Jun 13;
doi: 10.1038/s41598-018-27258-8
PMID: 29899432

DLX3-Dependent STAT3 Signaling in Keratinocytes Regulates Skin Immune Homeostasis.

Bhattacharya S, Kim JC, Ogawa Y, Nakato G, Nagle V, Brooks SR, Udey MC, Morasso MI
The Journal of investigative dermatology.
2018 May;
doi: 10.1016/j.jid.2017.11.033
PMID: 29246798

Genetic variants in pachyonychia congenita-associated keratins increase susceptibility to tooth decay.

Duverger O, Carlson JC, Karacz CM, Schwartz ME, Cross MA, Marazita ML, Shaffer JR, Morasso MI
PLoS genetics.
2018 Jan;
doi: 10.1371/journal.pgen.1007168
PMID: 29357356

Homeobox transcription factor DLX4 is not necessary for skin development and homeostasis.

Bhattacharya S, Duverger O, Brooks SR, Morasso MI
Experimental dermatology.
2018 Mar;
doi: 10.1111/exd.13503
PMID: 29380438

Policing Tumorigenesis within the Skin: Good Outs Bad.

Iglesias-Bartolome R, Morasso MI
Cell stem cell.
2017 Oct 5;
doi: 10.1016/j.stem.2017.08.019
PMID: 28985521

A novel DLX3-PKC integrated signaling network drives keratinocyte differentiation.

Palazzo E, Kellett MD, Cataisson C, Bible PW, Bhattacharya S, Sun HW, Gormley AC, Yuspa SH, Morasso MI
Cell death and differentiation.
2017 Apr;
doi: 10.1038/cdd.2017.5
PMID: 28186503

DLX3-Dependent Regulation of Ion Transporters and Carbonic Anhydrases is Crucial for Enamel Mineralization.

Duverger O, Ohara T, Bible PW, Zah A, Morasso MI
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research.
2017 Mar;
doi: 10.1002/jbmr.3022
PMID: 27760456

Mutations in TSPEAR, Encoding a Regulator of Notch Signaling, Affect Tooth and Hair Follicle Morphogenesis.

Peled A, Sarig O, Samuelov L, Bertolini M, Ziv L, Weissglas-Volkov D, Eskin-Schwartz M, Adase CA, Malchin N, Bochner R, Fainberg G, Goldberg I, Sugawara K, Baniel A, Tsuruta D, Luxenburg C, Adir N, Duverger O, Morasso M, Shalev S, Gallo RL, Shomron N, Paus R, Sprecher E
PLoS genetics.
2016 Oct;
doi: 10.1371/journal.pgen.1006369
PMID: 27736875

The homeoprotein DLX3 and tumor suppressor p53 co-regulate cell cycle progression and squamous tumor growth.

Palazzo E, Kellett M, Cataisson C, Gormley A, Bible PW, Pietroni V, Radoja N, Hwang J, Blumenberg M, Yuspa SH, Morasso MI
2016 Jun 16;
doi: 10.1038/onc.2015.380
PMID: 26522723

Keratins as components of the enamel organic matrix.

Duverger O, Beniash E, Morasso MI
Matrix biology : journal of the International Society for Matrix Biology.
2016 May-Jul;
doi: 10.1016/j.matbio.2015.12.007
PMID: 26709044

Calmodulin 4 is dispensable for epidermal barrier formation and wound healing in mice.

Lessard JC, Kalinin A, Bible PW, Morasso MI
Experimental dermatology.
2015 Jan;
doi: 10.1111/exd.12568
PMID: 25316000

Hair keratin mutations in tooth enamel increase dental decay risk.

Duverger O, Ohara T, Shaffer JR, Donahue D, Zerfas P, Dullnig A, Crecelius C, Beniash E, Marazita ML, Morasso MI
The Journal of clinical investigation.
2014 Dec;
doi: 10.1172/JCI78272
PMID: 25347471

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YouTube Video | July 25, 2018

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Research Brief | October 27, 2014

Research on Keratins Reveals Unexpected Link Between Hair Disorders and Dental Decay

Keratins are proteins that are key structural components of hair, nails, and the skin’s outer layer.

Last Updated: May 2020