Loss of serum response factor in keratinocytes results in hyperproliferative skin disease in mice
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
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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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 4

Disruption of the actin cytoskeleton and reduced cell-cell and cell-matrix contacts in Srf mutant mice.

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Disruption of the actin cytoskeleton and reduced cell-cell and cell-matr...
(A) Phalloidin-FITC staining of skin sections of control and Srf mutant mice at P14 shows markedly reduced levels of polymerized actin (F-actin) in lesions of Srf mutant skin (upper panels). Immunofluorescence staining for E-cadherin shows membrane localization in skin of control and Srf mutant mice (lower panels). Dotted lines indicate the basement membrane. Scale bar: 20 μm. (B–E) Ultrastructural analysis of control and Srf mutant epidermis at P14. (B) Keratinocytes in the basal cell layer of lesional Srf mutant epidermis are strongly enlarged and lack most cell-cell contacts compared with control skin, in which basal keratinocytes are small and densely packed. Arrows indicate the basement membrane. (C) Stratum corneum (sc) of lesional Srf mutant epidermis is thicker and less compact than stratum corneum of control epidermis. (D) Epidermal lesions of Srf mutant skin show areas with defective hemidesmosomes (arrows). Note that collagen bundles below the basement membrane are absent in Srf mutant skin. (E) Desmosomes (arrows) are markedly reduced in Srf mutant skin, and cell-cell contacts are largely absent. (F and G) Morphometric analysis confirmed a distinct reduction of the number of desmosomes (F), while no change of the mean length of single desmosomes could be found (G). Error bars indicate SD. Scale bars: 5 μm (B and C); 1 μm (D and E). ***P ≤ 0.001.