Hesser Boris A, Henschel Oliver, Witzemann Veit
Max-Planck-Institut für medizinische Forschung, Jahnstrasse 29, 69120 Heidelberg, Germany.
Mol Cell Neurosci. 2006 Mar;31(3):470-80. doi: 10.1016/j.mcn.2005.10.020. Epub 2005 Dec 7.
The muscle-specific-kinase MuSK is required for the formation of acetylcholine receptor clusters during embryonic development, but its physiological role in adult muscle is not known. We used the loxP/Cre system in mice to conditionally inactivate MuSK whereby expression of Cre recombinase increases during postnatal development. The MuSK-inactivated mice develop myasthenic symptoms and die prematurely due to severe muscle weakness. The postnatal inactivation of MuSK causes loss of acetylcholine receptors and disassembly of the postsynaptic organization and innervating axons retract but start to grow and branch extensively. Due to the mosaic expression of Cre recombinase, MuSK is not globally inactivated and new synapses are formed aberrantly patterned across the diaphragm. Our findings demonstrate that MuSK kinase activity is required throughout postnatal development to hold up MuSK and AChR levels at endplates. Thus, MuSK and AChR together maintain the functional and structural integrity of the postsynaptic architecture and prevent axon growth.
肌肉特异性激酶MuSK在胚胎发育过程中对于乙酰胆碱受体簇的形成是必需的，但其在成年肌肉中的生理作用尚不清楚。我们利用小鼠中的loxP/Cre系统有条件地使MuSK失活，从而在出生后发育过程中Cre重组酶的表达增加。MuSK失活的小鼠出现肌无力症状，并因严重的肌肉无力而过早死亡。MuSK在出生后的失活导致乙酰胆碱受体丧失，突触后组织解体，支配轴突回缩，但随后开始广泛生长和分支。由于Cre重组酶的镶嵌表达，MuSK并非完全失活，新的突触在横膈膜上异常形成。我们的研究结果表明，在出生后整个发育过程中都需要MuSK激酶活性来维持终板处MuSK和AChR的水平。因此，MuSK和AChR共同维持突触后结构的功能和结构完整性，并阻止轴突生长。
