Msx homeobox genes inhibit differentiation through upregulation of cyclin D1

During development, patterning and morphogenesis of tissues are intimately coordinated through control of cellular proliferation and differentiation. We describe a mechanism by which vertebrate Msx homeobox genes inhibit cell ular differentiation by regulation of the cell cycle. We show that misexpre ssion of Msx1 via retroviral gene transfer inhibits differentiation of mult iple mesenchymal and epithelial progenitor cell types in culture, This acti vity of Msx1 is associated with its ability to upregulate cyclin DI express ion and Cdk4 activity, while Msx1 has minimal effects on cellular prolifera tion. Transgenic mice that express Msx1 under the control of the mouse mamm ary tumor virus long terminal repeat (MMTV LTR) display impaired differenti ation of the mammary epithelium during pregnancy, which is accompanied by e levated levels of cyclin DI expression. We propose that Msx1 gene expressio n maintains cyclin DI expression and prevents exit from the cell cycle, the reby inhibiting terminal differentiation of progenitor cells. Our model pro vides a framework for reconciling the mutant phenotypes of Msx and other ho meobox genes with their functions as regulators of cellular proliferation a nd differentiation during embryogenesis.