THE E-PROTEIN CTP4 AND ACETYLCHOLINE-RECEPTOR EXPRESSION IN DEVELOPMENT AND DENERVATION SUPERSENSITIVITY

Motor activity blocks the extrasynaptic expression of many genes in sk eletal muscle, including those encoding ion channels, receptors, and a dhesion molecules. Denervation reinduces transcription throughout the multinucleated myofiber, restoring the developmental pattern of expres sion, especially of the genes coding for the acetylcholine receptor. A screen for trans-acting factors binding to the enhancer region of the cu-subunit gene of the acetylcholine receptor identified CTF4, a ubiq uitously expressed and alternatively spliced chicken homologue of the human E protein transcription factor HTF4/HEB, Expression of the CTF4 locus closely parallels that of myogenin and acetylcholine receptor du ring development and maturation of skeletal muscle, but transcription is not similarly regulated by neuronal cues. Alternative splicing with in the region encoding the transactivation domain generates two CTF4 i soforms with different tissue distributions, but similar binding affin ities for the acetylcholine receptor cu-subunit enhancer and similar t ranscriptional potential when complexed to myogenin, Direct injection of a myogenin, but not a MyoD, antisense expression vector into denerv ated skeletal muscle caused a significant decrease in the transcriptio nal activation of a depolarization-sensitive reporter gene. Similarly, injection of a CTF4, but less so of an E12, antisense expression vect or impaired the denervation response, further implicating the involvem ent of a myogenin/CTF4 heterodimer in the expression of AChR genes in vivo.