Changing a limb muscle growth program into a resorption program.
Transgenic Xenopus laevis tadpoles that express a dominant negative form of the thyroid hormone receptor (TRDN) controlled by the cardiac actin muscle promoter (pCar) develop with very little limb muscle. Under the control of the tetracycline system the transgene can be induced at will by adding doxycycline to the rearing water. Pre-existing limb muscle fibers begins to disintegrate within 2 days after up-regulation of the TRDN transgene. The muscle cells do not die even after weeks of transgene exposure when the myofibrils have degenerated completely and the tadpole is nearing death. A microarray analysis after 2 weeks of exposure to the transgene identified 24 muscle genes whose expression was altered in such a way that they might cause the muscle phenotype. These candidate genes are normally activated in growing limb muscle but they are repressed by the TRDN transgene. Several of these genes have been implicated in mammalian myopathies. However, the expression of only one of these genes, calsequestrin, is down-regulated in 1 day and therefore might initiate the degeneration. Calsequestrin is one of several affected genes that encode proteins involved in calcium sequestration, transport and utilization in muscle suggesting that uncontrolled calcium influx into the growing limb muscle fibers causes rhabdomyolysis. Many of the same genes that are down-regulated in the tail at the peak of metamorphic climax just before it is resorbed are suppressed in the transgenic limb muscle in effect turning the limb growth program into a tail resorption program.
Cai
Liquan
L
Carnegie Institution, 3520 San Martin Dr. Baltimore, MD 21218, USA.
Das
Biswajit
B
Brown
Donald D
DD
D000818:Animals; D030801:Animals, Genetically Modified; D020869:Gene Expression Profiling; D018014:Gene Transfer Techniques; D017403:In Situ Hybridization; D007814:Larva / Q000254:growth & development; D008675:Metamorphosis, Biological / Q000235:genetics; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000254:growth & development*; D009133:Muscular Atrophy / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism*; D014982:Xenopus laevis / Q000235:genetics / Q000254:growth & development*
D009124:Muscle Proteins; D037021:Thyroid Hormone Receptors alpha