Novel functions for the Hexapeptide motif in controlling Hox protein function. Y. Graba¹, M. Affolter², A. Fabre¹, J. Pradel¹, H. Berenger¹, S. Merabet². 1) LGPD/IBDM, CNRS, Marseille, France; 2) Biozentrum, Univ of Basel, Switzerland.

   Hox genes encode evolutionarily conserved transcription factors controlling diversified morphology in development and evolution. Although the Hexapeptide (HX) has been recognized as early as the Homeodomain as a landmark for Hox proteins, the in vivo function of the HX motif has been poorly investigated. Most studies have focused on its function in raising Hox DNA binding specificity, by recruiting the Exd/Pbx cofactors. Our functional analysis of the AbdA HX motif has revealed several unexpected features. First, mutation of the HX does not alleviate the capacity of AbdA to interact with Exd. Second, the analysis of wg and dpp target gene regulation has shown that the HX does not control AbdA DNA binding, but defines whether AbdA acts as a transcriptional activator or repressor. Third, at least in the regulation of dpp, the activity of the HX motif is exd independent. Finally, the HX acts in concert with a short evolutionary conserved motif lying in the linker region, acting together as hierachicaly organised regulatory modules within an intramolecular regulatory circuit that control AbdA activation/repression switch (Merabet et al., Dev. Cell, May 2003). We are now addressing to what extent our findings more largely applies to other Hox proteins, and why mutation of the HX in several Hox proteins does not alleviate interaction with Exd. In the case of AbdA, we found that this relies on the duplication of the HX motif. Current analysis should establish whether the duplication of the motif underlies acquisition of specialised functions.