Pax3 modulates expression of the c-Met receptor during limb muscle development
Pax3 modulates expression of the c-Met receptor during limb muscle development
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DOI：
10.1073/pnas.93.9.4213
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发表时间：
1996-04-30
影响因子：
11.1
通讯作者：
Maas, RL
中科院分区：
文献类型：
--
作者：
Epstein, JA;Shapiro, DN;Maas, RL
Pax 3是一种转录因子，其表达已被用作在侧体节中产生的肌源性前体细胞的标志物，所述肌源性前体细胞注定迁移到并填充肢体肌肉组织。越来越多的证据表明，胚胎学起源的轴和approxular肌肉是不同的，和四肢肌肉异常的小鼠和人类窝藏Pax 3突变支持这种区别。Pax 3影响肢体肌肉发育的机制尚不清楚。由c-met原癌基因编码的肝细胞生长因子/分散因子的酪氨酸激酶受体也在肢体肌肉祖细胞中表达，并且与Pax-3一样，是小鼠肢体肌肉发育所需的。在这里，我们发现，c-met表达显着减少，在侧皮肌节的斑点胚胎缺乏Pax 3。我们表明，Pax 3可以刺激c-met在培养细胞中的表达，我们确定了一个潜在的Pax 3结合位点的人c-MET启动子，可能有助于直接转录调控。此外，我们还发现，由激活PAX 3的t（2;13）染色体易位引起的横纹肌肉瘤患者的几种细胞系表达c-MET，而那些没有易位的横纹肌肉瘤细胞系则不表达c-MET。这些结果与Pax 3调节外侧皮肌节中c-met表达的模型一致，这是这些肌原性前体适当迁移到肢体所需的功能，其中c-met（肝细胞生长因子/分散因子）的配体以高水平表达。
Pax3 is a transcription factor whose expression has been used as a marker of myogenic precursor cells arising in the lateral somite destined to migrate to and populate the limb musculature. Accruing evidence indicates that the embryologic origins of axial and appendicular muscles are distinct, and limb muscle abnormalities in both mice and humans harboring Pax3 mutations support this distinction. The mechanisms by which Pax3 affects limb muscle development are unknown. The tyrosine kinase receptor for hepatocyte growth factor/scatter factor encoded by the c-met protooncogene is also expressed in limb muscle progenitors and, like Pax-3, is required in the mouse for limb muscle development. Here, we show that c-met expression is markedly reduced in the lateral dermomyotome of Splotch embryos lacking Pax3. We show that Pax3 can stimulate c-met expression in cultured cells, and we identify a potential Pax3 binding site in the human c-MET promoter that may contribute to direct transcriptional regulation. In addition, we have found that several cell lines derived from patients with rhabdomyosarcomas caused by a t(2;13) chromosomal translocation activating PAX3 express c-MET, whereas those rhabdomyosarcoma cell lines examined without the translocation do not. These results are consistent with a model in which Pax3 modulates c-met expression in the lateral dermomyotome, a function that is required for the appropriate migration of these myogenic precursors to the Limb where the ligand for c-met (hepatocyte growth factor/scatter factor) is expressed at high levels.