Serum response factor controls transcriptional network regulating epidermal function and hair follicle morphogenesis

Congxing Lin, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Anna Hindes, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Carole J. Burns, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Aaron C. Koppel, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Alexi Kiss, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Yan Yin, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Liang Ma, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA.
Miroslav Blumenberg, R. O. Perelman Department of Dermatology, NYU School of Medicine, New York, New York, USA.
Denis Khnykin, Department of Pathology and Centre for Immune Regulation, University Hospital and University of Oslo, Oslo, Norway.
Frode L. Jahnsen, Department of Pathology and Centre for Immune Regulation, University Hospital and University of Oslo, Oslo, Norway.
Seth D. Crosby, Department of Genetics, Washington University School of Medicine, St Louis, Missouri, USA.
Narendrakumar Ramanan, Department of Anatomy and Neurobiology, Washington University School of Medicine, St Louis, Missouri, USA.
Tatiana Efimova, Division of Dermatology, Department of Internal Medicine, Washington University School of Medicine, St Louis, Missouri, USA. Electronic address: tefimova@dom.wustl.edu.

Document Type

Journal Article

Publication Date

11-16-2012

Journal

The Journal of investigative dermatology

Volume

133

Issue

3

DOI

10.1038/jid.2012.378

Abstract

Serum response factor (SRF) is a transcription factor that regulates the expression of growth-related immediate-early, cytoskeletal, and muscle-specific genes to control growth, differentiation, and cytoskeletal integrity in different cell types. To investigate the role for SRF in epidermal development and homeostasis, we conditionally knocked out SRF in epidermal keratinocytes. We report that SRF deletion disrupted epidermal barrier function leading to early postnatal lethality. Mice lacking SRF in epidermis displayed morphogenetic defects, including an eye-open-at-birth phenotype and lack of whiskers. SRF-null skin exhibited abnormal morphology, hyperplasia, aberrant expression of differentiation markers and transcriptional regulators, anomalous actin organization, enhanced inflammation, and retarded hair follicle (HF) development. Transcriptional profiling experiments uncovered profound molecular changes in SRF-null E17.5 epidermis and revealed that many previously identified SRF target CArG box-containing genes were markedly upregulated in SRF-null epidermis, indicating that SRF may function to repress transcription of a subset of its target genes in epidermis. Remarkably, when transplanted onto nude mice, engrafted SRF-null skin lacked hair but displayed normal epidermal architecture with proper expression of differentiation markers, suggesting that although keratinocyte SRF is essential for HF development, a cross-talk between SRF-null keratinocytes and the surrounding microenvironment is likely responsible for the barrier-deficient mutant epidermal phenotype.

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