ALX-4, A TRANSCRIPTIONAL ACTIVATOR WHOSE EXPRESSION IS RESTRICTED TO SITES OF EPITHELIAL-MESENCHYMAL INTERACTIONS

We have recently demonstrated that the retinoblastoma family of negati ve cell cycle regulators can form complexes with a class of developmen tal factors which contain paired-like (PL) homeodomains (Wiggan et al, [1998] Oncogene 16:227-236), Our screens led to the isolation of a no vel PL-homeodomain protein which had been isolated independently by an other group and called Alx-4 (Qu et al. [1997] Development 124:3999-40 08), Mice homozygous for a targeted null mutation of Alx-4 have severa l abnormalities, including preaxial polydactyly, suggesting that Alx-4 plays a role in pattern formation in limb buds. In data that we prese nt here, we show that Alx-4 is expressed in mesenchymal condensations of a diverse group of tissues whose development is dependent on epithe lial-mesenchymal interactions, many of which are additionally dependen t on expression of the HMG-box-containing protein, LEF-1. Alx-4-expres sing tissues include osteoblast precursors of most bones, the dermal p apilla of hair and whisker follicles, the dental papilla of teeth, and a subset of mesenchymal cells in pubescent mammary glands. We show fu rther that Alx-4 strongly activates transcription from a promoter cont aining the homeodomain binding site, P2. Optimal activation requires s pecific sequences in the N-terminal portion of Alx-4 as well as a prol ine-rich region downstream of the PL-homeodomain, but not the paired-t ail at the C terminus. Taken together, our results demonstrate that Al x-4 is a potent transcriptional activator that is expressed at sites o f epithelial-mesenchymal interactions during murine embryonic developm ent. Dev. Dyn. 1998;213:159-169. (C) 1998 Wiley-Liss, Inc.