Abstract

Transforming growth factor-beta-activated kinase 1 (TAK1) is a member of the mitogen-activated protein (MAP) kinase family and is an upstream signaling molecule of nuclear factor-kappaB (NF-kappaB). Given that NF-kappaB regulates keratinocyte differentiation and apoptosis, TAK1 may be essential for epidermal functions. To test this, we generated keratinocyte-specific TAK1-deficient mice from Map3k7(flox/flox) mice and K5-Cre mice. The keratinocyte-specific TAK1-deficient mice were macroscopically indistinguishable from their littermates until postnatal day 2 or 3, when the skin started to roughen and wrinkle. This phenotype progressed, and the mice died by postnatal day 7. Histological analysis showed thickening of the epidermis with foci of keratinocyte apoptosis and intra-epidermal micro-abscesses. Immunohistochemical analysis showed that the suprabasal keratinocytes of the TAK1-deficient epidermis expressed keratin 5 and keratin 14, which are normally confined to the basal layer. The expression of keratin 1, keratin 10, and loricrin, which are markers for the suprabasal and late phase differentiation of the epidermis, was absent from the TAK1-deficient epidermis. Furthermore, the TAK1-deficient epidermis expressed keratin 16 and had an increased number of Ki67-positive cells. These data indicate that TAK1 deficiency in keratinocytes results in abnormal differentiation, increased proliferation, and apoptosis in the epidermis. However, the keratinocytes from the TAK1-deficient epidermis induced keratin 1 in suspension culture, indicating that the TAK1-deficient keratinocytes retain the ability to differentiate. Moreover, the removal of TAK1 from cultured keratinocytes of Map3k7(flox/flox) mice resulted in apoptosis, indicating that TAK1 is essential for preventing apoptosis. In conclusion, TAK1 is essential in the regulation of keratinocyte growth, differentiation, and apoptosis.

Highlights

  • In the epidermis, NF-␬B is found in the cytoplasm of basal cells [1]

  • Generating Mice with Keratinocyte-specific Transforming growth factor-␤-activated kinase 1 (TAK1) Deficiency—The germ line targeting of the Map3k7 gene encoding TAK1 results in embryonic lethality [15]; we generated keratinocyte-specific TAK1-deficient mice (Fig. 1) by breeding Map3k7 flox/flox mice with mice carrying the Cre transgene under the control of the keratin 5 promoter (K5-Cre) [16]

  • Western blot analysis and Reverse Transcriptase (RT)-PCR showed the Cre-mediated deletion of TAK1 in keratinocytes from K5-Cre/Map3k7 flox/flox mice at birth (Fig. 1, D and E)

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Summary

Introduction

NF-␬B is found in the cytoplasm of basal cells [1]. The functional blockade of NF-␬B by expressing dominant negative NF-␬B in transgenic mouse epidermis produced a hyperplastic epithelium in vivo [1]. Given that TAK1 is an upstream signaling molecule of the NF-␬B pathway, TAK1 might regulate keratinocyte growth, differentiation, and apoptosis. We generated keratinocyte-specific TAK1-deficient mice by using Cre-recombinase transgenic mice under the control of the K5 promoter.

Results
Conclusion
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