The E protein CTF4 and acetylcholine receptor expression in development and denervation supersensitivity.
Motor activity blocks the extrasynaptic expression of many genes in skeletal muscle, including those encoding ion channels, receptors, and adhesion molecules. Denervation reinduces transcription throughout the multinucleated myofiber, restoring the developmental pattern of expression, especially of the genes coding for the acetylcholine receptor. A screen for trans-acting factors binding to the enhancer region of the alpha-subunit gene of the acetylcholine receptor identified CTF4, a ubiquitously 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 during development and maturation of skeletal muscle, but transcription is not similarly regulated by neuronal cues. Alternative splicing within the region encoding the transactivation domain generates two CTF4 isoforms with different tissue distributions, but similar binding affinities for the acetylcholine receptor alpha-subunit enhancer and similar transcriptional potential when complexed to myogenin. Direct injection of a myogenin, but not a MyoD, antisense expression vector into denervated skeletal muscle caused a significant decrease in the transcriptional activation of a depolarization-sensitive reporter gene. Similarly, injection of a CTF4, but less so of an E12, antisense expression vector impaired the denervation response, further implicating the involvement of a myogenin/CTF4 heterodimer in the expression of AChR genes in vivo.
Neville
C M
CM
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, Massachusetts 02129-2060, USA.
Choe
Y H
YH
Lee
Y S
YS
Spinner
D
D
Tsay
H J
HJ
Schmidt
J
J
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D030161:Avian Proteins; D001483:Base Sequence; D051792:Basic Helix-Loop-Helix Proteins; D001921:Brain / Q000196:embryology / Q000378:metabolism; D002645:Chickens; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D003714:Denervation; D019281:Dimerization; D018507:Gene Expression Regulation, Developmental; D018257:Helix-Loop-Helix Motifs; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000196:embryology / Q000294:innervation / Q000378:metabolism; D018008:Myogenin / Q000378:metabolism; D011950:Receptors, Cholinergic / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism
D030161:Avian Proteins; D051792:Basic Helix-Loop-Helix Proteins; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D018008:Myogenin; D011950:Receptors, Cholinergic; D014157:Transcription Factors; C503799:MYOG protein, human; C503801:Myog protein, mouse; C074325:CTF4 protein, Gallus gallus