Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice
Heidi Koegel, … , Alfred Nordheim, Sabine Werner
Heidi Koegel, … , Alfred Nordheim, Sabine Werner
Published March 23, 2009
Citation Information: J Clin Invest. 2009;119(4):899-910. https://doi.org/10.1172/JCI37771.
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Research Article Dermatology

Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice

Abstract

The transcription factor serum response factor (SRF) plays a crucial role in the development of several organs. However, its role in the skin has not been explored. Here, we show that keratinocytes in normal human and mouse skin expressed high levels of SRF but that SRF expression was strongly downregulated in the hyperproliferative epidermis of wounded and psoriatic skin. Keratinocyte-specific deletion within the mouse SRF locus during embryonic development caused edema and skin blistering, and all animals died in utero. Postnatal loss of mouse SRF in keratinocytes resulted in the development of psoriasis-like skin lesions. These lesions were characterized by inflammation, hyperproliferation, and abnormal differentiation of keratinocytes as well as by disruption of the actin cytoskeleton. Ultrastructural analysis revealed markedly reduced cell-cell and cell-matrix contacts and loss of cell compaction in all epidermal layers. siRNA-mediated knockdown of SRF in primary human keratinocytes revealed that the cytoskeletal abnormalities and adhesion defects were a direct consequence of the loss of SRF. In contrast, the hyperproliferation observed in vivo was an indirect effect that was most likely a consequence of the inflammation. These results reveal that loss of SRF disrupts epidermal homeostasis and strongly suggest its involvement in the pathogenesis of hyperproliferative skin diseases, including psoriasis.

Authors

Heidi Koegel, Lukas von Tobel, Matthias Schäfer, Siegfried Alberti, Elisabeth Kremmer, Cornelia Mauch, Daniel Hohl, Xiao-Jing Wang, Hans-Dietmar Beer, Wilhelm Bloch, Alfred Nordheim, Sabine Werner

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Figure 1

Downregulation of SRF expression in hyperproliferative epidermis.

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Downregulation of SRF expression in hyperproliferative epidermis. (A) SR...
(A) SRF expression in murine (m) and human (h) primary (1°) keratinocytes (kerat) and in murine cardiac muscle (card) shown by Western blotting using a rat anti-SRF mAb (2C5). (B) Immunohistochemical analysis of sections from mouse and human skin using the 2C5 antibody shows nuclear localization of SRF in the epidermis (epi). hf, hair follicle. Scale bar: 50 μm. (C) Immunofluorescence stainings of SRF (green, middle and lower panels) show nuclear localization of SRF in epidermal keratinocytes of a healthy patient. Nuclear SRF was not detected in lesional skin of a psoriatic patient. PI-stained sections are shown at low magnification in the upper panels. Representative biopsies (from 5 healthy and 5 psoriatic patients) are shown. Control skin, yellow from double staining with propidium iodide (PI), red. d, dermis. Scale bars: 100 μm (upper panels); 20 μm (middle and lower panels). (D) Immunofluorescence stainings of SRF (middle panels and, in combination with PI, lower panels) show nuclear localization in keratinocytes of normal mouse skin but reduced staining in the hyperproliferative epithelium of 5-day wounds (5 dw). PI-stained sections are shown at low magnification in the upper panels. Asterisk indicates area of hyperproliferative epithelium at the wound edge shown at higher magnification in the lower panels. g, granulation tissue; he, hyperproliferative epithelium. Scale bars: 100 μm (upper panels); 20 μm (middle and lower panels). Dotted lines indicate basement membrane. (E and F) Western blot analysis of SRF using lysates from 3 healthy patients (ctrl) and affected skin of 3 psoriatic (psor) patients (E) or lysates of normal mouse skin and excisional wounds (F). (A, E, and F) Asterisks denote an additional band that is recognized by the anti-SRF antibody. GAPDH was used as a loading control.