THE PRODUCT OF THE MOUSE NUDE LOCUS WHN, REGULATES THE BALANCE BETWEEN EPITHELIAL-CELL GROWTH AND DIFFERENTIATION

Mutations in the winged-helix nude (whn) gene result in the nude mouse and rat phenotypes. The pleiotropic nude phenotype which affects the hair, skin, and thymus suggests that rt hn plays a pivotal role in the development and/or maintenance of these organs. However, little is kn own about whn function in these organs. We show here that in skin whn is specifically expressed in epithelial cells and not the mesenchymal cells, and using a hair reconstitution assay, we demonstrate that the abnormal nude mouse hair development is attributable to a functional d efect of the epithelial cells. Examination of nude mouse primary kerat inocytes in culture revealed that these cells have an increased propen sity to differentiate in an abnormal fashion, even under conditions th at promote proliferation. Furthermore, nude mouse keratinocytes displa yed a 100-fold increased sensitivity to the growth-inhibitor/different iation effects of the phorbol ester TPA. In parallel with these findin gs, we directly show that tt hn functions as a transcription factor th at can specifically suppress expression of differentiation/TPA-respons ive genes. The region of Whn responsible for these effects was mapped to the carboxy-terminal transactivating domain. These results establis h whn as a key regulatory factor involved in maintaining the balance b etween keratinocyte growth and differentiation. The general implicatio ns of these findings for an epithelial self-renewal model will be disc ussed.