Overview

The pathways that regulate epidermal differentiation and the formation of a functional skin barrier have been a central topic of investigation in epidermal biology. Our research efforts have focused on characterizing the transcriptional regulatory networks and signaling pathways linked to epidermal differentiation and wound healing.

Epidermal Differentiation and Inflammatory Disorders

Epidermal homeostasis results from a balance between keratinocyte proliferation and differentiation, with alterations to this balance leading to cancer. Using animal models, we have demonstrated the central role of the 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 STAT3-dependent signaling pathways that are crucial to maintaining cutaneous homeostasis. The epidermal conditional deletion of DLX3 leads to the disruption of skin barrier formation. It is linked to epidermal hyperplasia and the development of an inflammatory response, characterized by the accumulation of IL-17-producing T cells. Our studies also provide a novel understanding of the signaling networks regulating squamous tumorigenesis.

Wound Healing

Illustrated cross-section of inflamed, normal and wounded skin.
Schematic diagram showing epidermal differentiation, inflammation and wounding.

Oral wounds are considered an ideal prototype of adult tissue repair due to their intrinsic ability for scarless accelerated wound healing. Our studies have shown that wound-activated transcriptional networks are active in oral mucosa at a basal state, priming this tissue for wound repair by controlling epithelial cell differentiation. We have determined the capability of the SOX2 and PITX1 transcription factors to reprogram cutaneous keratinocytes for accelerated wound resolution. Furthermore, we found that SOX2 promotes keratinocyte migration and angiogenesis through the upregulation of EGFR ligands and activation of the ERK/MAPK pathway. In contrast to acute cutaneous and oral wounds, chronic non-healing wounds do not resolve and are characterized by deregulated inflammation. This is due to ineffective recruitment and activation of macrophages and neutrophils. We are currently focused on identifying pathways responsible for the downregulation of inflammation that will be pivotal for diagnostics and the development of potential therapeutics.

Ectodermal Dysplasias and Ectodermal Appendage Development

Ectodermal dysplasias are a group of heritable pathological disorders that result from anomalies in epithelial/mesenchymal-derived appendage formation. The importance of DLX3 is underscored by the effects of mutations found 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. 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.

Contact Us

Nikki Eiland

Sr. Administrative Assistant
9000 Rockville Pike
Building 50, Room 1518
Bethesda MD 20892

Core Research Facilities

Labs at the NIAMS are supported by the following state-of-the-art facilities and services:

Staff

Former Lab Members

Postdoctoral Fellows

  • Daniela Grassini, Visiting Fellow (2018-2021)
  • Akihiko Uchiyama, Visiting Fellow, JSPS Fellowship (2016-2019)
  • Shreya Bhattacharya, Visiting Fellow (2014-2017)
  • Kathleen Baysac, IRTA Fellow (2015-2017)
  • Ramiro Iglesias-Bartolome, Research Fellow (2015-2016)
  • Paul Bible, IRTA Fellow (2013-2015)
  • Jin-Chul Kim, Visiting Fellow (2010-2015)
  • Juliane Lessard, IRTA Fellow (2013-2014)
  • Elisabetta Palazzo, Visiting Fellow (2011-2014)
  • Juliane Isaac, Visiting Fellow (2009-2013)
  • Junko Okano, Visiting Fellow (2008-2012)
  • Olivier Duverger, Visiting Fellow (2006-2011)
  • Joonsung Hwang, Visiting Fellow (2004-2011)
  • Oleksandr Kalinin, Visiting Fellow (2004-2008)
  • Valentina Pietroni, Visiting Fellow (2006-2008)
  • Nadezda Radoja, IRTA Fellow (2004-2006)
  • Meeyul Hwang, Visiting Fellow (2001-2005)
  • Janine Bryan, IRTA Fellow (2000-2002)
  • Geon Tae Park, Visiting Fellow (2000-2003)

Postbaccalaureate Fellows

  • Emma Hope (2020-2022)
  • Stephen Worrell (2020-2021)
  • Michael Cross (2017-2019)
  • Rose Graf (2017-2018)
  • Veronica Nagle (2016-2017)
  • Maya Evanitsky (2016-2017)
  • Chelsea Karacz (2015-2017)
  • Meghan Kellett (2013-2016)
  • Victoria Sun (2014-2015)
  • Takahiro O'Hara (2012-2014)
  • Anna Gormley (2012-2013)
  • Claire Levy (2011-2012)
  • Angela Zah (2010-2012)
  • Anne Bartels (2009-2010)
  • Ryosuke Kita (2009-2010)
  • Nicole Gentile (2007-2008)
  • Susie Chen (2007-2008)
  • Delia Lee (2006-2007)
  • Sarah-Jo Stimpson (2005-2006)
  • Charlene Rivera (2001-2002)
  • Taraneh Mehrani (2000-2001)

Research Fellows

  • Deepti Bajpai, Research Fellow (2017-2022)

Staff Scientist

  • Olivier Duverger, Staff Scientist (2011-2017)

Image & Media Gallery

Scientific Publications

Selected Recent Publications

Keratin 75 Is a Component of the LINC Complex and Has an Essential Role in Mediating the SOX2 Rapid Healing Response During Wound Repair.

Sawaya AP, Uchiyama A, Hope E, Bajpai D, Worrell S, Cross M, Beniash E, Jenkins LM, Duverger O, Morasso MI
J Invest Dermatol.
2022 Sep 26;
pii: S0022-202X(22)01933-9. doi: 10.1016/j.jid.2022.08.054
PMID: 36174715

Intrinsic Networks Regulating Tissue Repair: Comparative Studies of Oral and Skin Wound Healing.

Overmiller AM, Sawaya AP, Hope ED, Morasso MI
Cold Spring Harb Perspect Biol.
2022 Nov 1;
14(11).
doi: 10.1101/cshperspect.a041244
PMID: 36041785

Transcriptional Regulation of Jaw Osteoblasts: Development to Pathology.

Nassif A, Lignon G, Asselin A, Zadikian CC, Petit S, Sun HW, Klein C, Ferré FC, Morasso MI, Berdal A, Fournier BPJ, Isaac J
J Dent Res.
2022 Jul;
101(7).
doi: 10.1177/00220345221074356
PMID: 35148649

Do DLX3 and CD271 Protect Human Keratinocytes from Squamous Tumor Development?

Palazzo E, Marconi A, Pincelli C, Morasso MI
Int J Mol Sci.
2019 Jul 19;
20(14).
doi: 10.3390/ijms20143541
PMID: 31331058

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
Am J Med Genet A.
2019 Mar;
179(3).
doi: 10.1002/ajmg.a.61045
PMID: 30703280

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
Sci Rep.
2018 Jun 13;
8(1).
doi: 10.1038/s41598-018-27258-8
PMID: 29899432

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

Bhattacharya S, Duverger O, Brooks SR, Morasso MI
Exp Dermatol.
2018 Mar;
27(3).
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;
21(4).
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 Differ.
2017 Apr;
24(4).
doi: 10.1038/cdd.2017.5
PMID: 28186503

Key Publications

FOXM1 network in association with TREM1 suppression regulates NET formation in diabetic foot ulcers.

Sawaya AP, Stone RC, Mehdizadeh S, Pastar I, Worrell S, Balukoff NC, Kaplan MJ, Tomic-Canic M, Morasso MI
EMBO Rep.
2022 Aug 3;
23(8).
doi: 10.15252/embr.202154558
PMID: 35856334

Human oral mucosa cell atlas reveals a stromal-neutrophil axis regulating tissue immunity.

Williams DW, Greenwell-Wild T, Brenchley L, Dutzan N, Overmiller A, Sawaya AP, Webb S, Martin D, NIDCD/NIDCR Genomics and Computational Biology
Cell.
2021 Jul 22;
184(15).
doi: 10.1016/j.cell.2021.05.013
PMID: 34129837

Loss of DLX3 tumor suppressive function promotes progression of SCC through EGFR-ERBB2 pathway.

Bajpai D, Mehdizadeh S, Uchiyama A, Inoue Y, Sawaya A, Overmiller A, Brooks SR, Hasneen K, Kellett M, Palazzo E, Motegi SI, Yuspa SH, Cataisson C,
Oncogene.
2021 May;
40(21).
doi: 10.1038/s41388-021-01802-9
PMID: 33947961

Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing.

Sawaya AP, Stone RC, Brooks SR, Pastar I, Jozic I, Hasneen K, O'Neill K, Mehdizadeh S, Head CR, Strbo N, Morasso MI, Tomic-Canic M
Nat Commun.
2020 Sep 16;
11(1).
doi: 10.1038/s41467-020-18276-0
PMID: 32938916

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
J Invest Dermatol.
2019 Aug;
139(8).
doi: 10.1016/j.jid.2019.02.004
PMID: 30772301

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

Duverger O, Cross MA, Smith FJD, Morasso MI
J Invest Dermatol.
2019 Jan;
139(1).
doi: 10.1016/j.jid.2018.07.005
PMID: 30009827

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,
Sci Transl Med.
2018 Jul 25;
10(451).
pii: eaap8798. doi: 10.1126/scitranslmed.aap8798
PMID: 30045979

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
J Invest Dermatol.
2018 May;
138(5).
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 Genet.
2018 Jan;
14(1).
doi: 10.1371/journal.pgen.1007168
PMID: 29357356

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
J Clin Invest.
2014 Dec;
124(12).
doi: 10.1172/JCI78272
PMID: 25347471

News & Highlights

NIAMS-Related Article | September 15, 2022

Overzealous Immune Cells Hamper Healing

For a type of wound that often plagues patients with diabetes, healing is no sure thing. IRP researchers recently identified why certain immune cells shift from helpful healers into saboteurs in those injuries.
NIAMS-Related Article | October 27, 2021

The mouth’s curative superpowers

Wounds in the mouth heal faster than in skin — and without scarring. Could unravelling the mechanisms that drive regeneration in the oral cavity lead to better wound therapies?
Spotlight on Research | November 2, 2020

Researchers Uncover Clues to Why Some Wounds Don’t Heal

Researchers identify defects in the wound healing process that might explain why diabetic foot ulcers heal slower or not at all.
NIH Research Matters | September 29, 2020

Poor immune response impairs diabetic wound healing

Researchers found that diabetic foot ulcers don’t recruit the immune cells necessary for normal wound healing.
YouTube Video | July 25, 2018

NIH Study Examines Processes Underlying Rapid Wound Healing in the Mouth

Researchers from the NIH’s NIAMS and the NIDCR have identified transcriptional regulators that prime the mouth’s muco