Targeted deletion of TGFβ1 in basal keratinocytes causes profound defects in stratified squamous epithelia and aberrant melanocyte migration

Fiona E. Chalmers, Justyn E. Dusold, Javed A. Shaik, Hailey A. Walsh, Adam B. Glick

Research output: Contribution to journalArticlepeer-review

Abstract

Transforming Growth Factor Beta 1 (TGFβ1) is a multifunctional cytokine that regulates proliferation, apoptosis, and epithelial-mesenchymal transition of epithelial cells. While its role in cancer is well studied, less is known about TGFβ1 and regulation of epithelial development. To address this, we deleted TGFβ1 in basal keratinocytes of stratified squamous epithelia. Newborn mice with a homozygous TGFβ1 deletion had significant defects in proliferation and differentiation of the epidermis and oral mucosa, and died shortly after birth. Hair follicles were sparse in TGFβ1 depleted skin and had delayed development. Additionally, the Wnt pathway transcription factor LEF1 was reduced in hair follicle bulbs and nearly absent from the basal epithelial layer. Hemizygous knockout mice survived to adulthood but were runted and had sparse coats. The skin of these mice had irregular hair follicle morphology and aberrant hair cycle progression, as well as abnormally high melanin expression and delayed melanocyte migration. In contrast to newborn TGFβ1 null mice, the epidermis was hyperproliferative, acanthotic and inflamed. Expression of p63, a master regulator of stratified epithelial identity, proliferation and differentiation, was reduced in TGFβ1 null newborn epidermis but expanded in the postnatal acanthotic epidermis of TGFβ1 hemizygous mice. Thus, TGFβ1 is both essential and haploinsufficient with context dependent roles in stratified squamous epithelial development and homeostasis.

Original languageEnglish (US)
Pages (from-to)9-23
Number of pages15
JournalDevelopmental Biology
Volume485
DOIs
StatePublished - May 2022

Bibliographical note

Funding Information:
This work was supported by the USDA National Institute of Food and Agriculture Federal Appropriations under Project PEN04607 and Accession number 1009993, and funding from the Department of Veterinary and Biomedical Sciences, Pennsylvania State University to AG. Initial work was supported by NIH grant R01 CA122109 and the Elsa U. Pardee Foundation to AG. FC was supported by a Postdoctoral Fellowship award from the Penn State Cancer Institute . The authors wish to acknowledge Dr. Stuart Yuspa for continued support.

Publisher Copyright:
© 2022 Elsevier Inc.

Keywords

  • Keratinocyte differentiation
  • Melanocytes
  • Stratified squamous epithelium
  • TGFβ signaling
  • Tissue homeostasis
  • Epithelium/metabolism
  • Keratinocytes
  • Epidermis/metabolism
  • Animals
  • Hair Follicle
  • Cell Differentiation
  • Mice
  • Carcinoma, Squamous Cell/metabolism

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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