OVEREXPRESSION OF MYOGENIN IN MUSCLES OF TRANSGENIC MICE - INTERACTION WITH ID-1, NEGATIVE CROSSREGULATION OF MYOGENIC FACTORS, AND INDUCTION OF EXTRASYNAPTIC ACETYLCHOLINE-RECEPTOR EXPRESSION
K. Gundersen et al., OVEREXPRESSION OF MYOGENIN IN MUSCLES OF TRANSGENIC MICE - INTERACTION WITH ID-1, NEGATIVE CROSSREGULATION OF MYOGENIC FACTORS, AND INDUCTION OF EXTRASYNAPTIC ACETYLCHOLINE-RECEPTOR EXPRESSION, Molecular and cellular biology, 15(12), 1995, pp. 7127-7134
To investigate the role of myogenin in regulating acetylcholine recept
or expression in adult muscle, this muscle-specific basic helix-loop-h
elix transcription factor was overexpressed in transgenic mice by usin
g regulatory elements conferring strong expression confined to differe
ntiated postmitotic muscle fibers. Many of the transgenic mice died du
ring the first postnatal week, but those that survived into adulthood
displayed normal muscle histology, gross morphology, and motor behavio
r. The mRNA levels of all five acetylcholine receptor subunits (alpha,
beta, gamma, delta, and epsilon) mere, however, elevated. Also, the l
evel of receptor protein was increased and high level of receptors wer
e present throughout the extrasynaptic surface membrane of the muscle
fibers. Thus, elevated levels of myogenin are apparently sufficient to
induce acetylcholine supersensitivity in normally innervated muscle o
f adult mice. The high neonatal mortality rate of the mice overexpress
ing myogenin hindered the propagation of a stable line. In an attempt
to increase survival, myogenin overexpressers were mated with a line o
f transgenic mice overexpressing Id-1, a negative regulator that inter
acts with the basic helix-loop-helix family of transcription factors.
The Id-1 transgene apparently worked as a second site suppressor and a
bolished the high rate of neonatal mortality, This effect indicates th
at Id-1 and myogenin interact directly or indirectly in these animals.
Further study indicated that myogenin overexpression had no effect on
the level of endogenous myogenin mRNA, while the levels of myoD and M
RF4 mRNAs were reduced. Overexpression of the negative regulator Id-1
increased the mRNA levels of all the myogenic factors, These findings
are consistent with a hypothesis suggesting that myogenic factors are
influenced by mechanisms that maintain cellular homeostasis.