NONMYOGENIC FACTORS BIND NICOTINIC ACETYLCHOLINE-RECEPTOR PROMOTER ELEMENTS REQUIRED FOR RESPONSE TO DENERVATION

Nicotinic acetylcholine receptors (AChRs) belong to a class of muscle proteins whose expression is regulated by muscle electrical activity. In innervated muscle fiber, AChR genes are transcriptionally repressed outside of the synapse, while after denervation they become reexpress ed throughout the fiber. The myogenic determination factors (MDFs) of the MyoD family have been shown to play a central role in this innerva tion-dependent regulation. In the chicken AChR alpha-subunit gene prom oter, two E-boxes that bind MDFs are necessary to achieve the enhancem ent of transcription following muscle denervation. However, the deleti on of promoter sequences located upstream to these E-boxes greatly imp airs the response to denervation (Bessereau, J, L,, Stratford-Perricau det, L, D,, Piette, J,, Le Poupon, C, and Changeux, J, P, (1994) Proc. Natl Acad. Sci, U, S, A. 91, 1304-1308), Here we identified two addit ional cia-regulatory elements of the alpha-subunit gene promoter that cooperate with the E-boxes in the denervation response. One region bin ds the Sp1 and Sp3 zinc finger transcription factors. The second regio n binds at least three distinct factors, among which we identified an upstream stimulatory factor, a b-ZIP-HLH transcription factor. We prop ose that among MDF-responsive muscle promoters, a specific combination between myogenic and nonmyogenic factors specify innervation-dependen t versus innervation-independent promoters.