PDF(Pubmed)
Abstract：
Gene regulatory networks that act upstream of skeletal muscle fate determinants are distinct in different anatomical locations. Despite recent efforts, a clear understanding of the cascade of events underlying the emergence and maintenance of the stem cell pool in specific muscle groups remains unresolved and debated. Here, we invalidated Pitx2 with multiple Cre-driver mice prenatally, postnatally, and during lineage progression. We showed that this gene becomes progressively dispensable for specification and maintenance of the muscle stem (MuSC) cell pool in extraocular muscles (EOMs) despite being, together with Myf5, a major upstream regulator during early development. Moreover, constitutive inactivation of Pax7 postnatally led to a greater loss of MuSCs in the EOMs compared to the limb. Thus, we propose a relay between Pitx2, Myf5 and Pax7 for EOM stem cell maintenance. We demonstrate also that MuSCs in the EOMs adopt a quiescent state earlier that those in limb muscles and do not spontaneously proliferate in the adult, yet EOMs have a significantly higher content of Pax7+ MuSCs per area pre- and post-natally. Finally, while limb MuSCs proliferate in the mdx mouse model for Duchenne muscular dystrophy, significantly less MuSCs were present in the EOMs of the mdx mouse model compared to controls, and they were not proliferative. Overall, our study provides a comprehensive in vivo characterisation of MuSC heterogeneity along the body axis and brings further insights into the unusual sparing of EOMs during muscular dystrophy.
摘要：
在骨骼肌命运决定子上游起作用的基因调控网络在不同的解剖位置是不同的。尽管最近的努力，对特定肌肉群中干细胞池出现和维持的潜在事件级联的清晰理解仍未解决和辩论.这里,我们在产前用多个Cre驱动小鼠使Pitx2无效，出生后,在谱系发展过程中。我们表明，尽管存在，但该基因对于眼外肌（EOM）中肌肉干（MuSC）细胞池的规范和维持逐渐变得可有可无，与Myf5一起，Myf5是早期开发期间的主要上游监管机构。此外，与肢体相比，Pax7的组成性失活导致EOM中MuSC的损失更大。因此，我们建议在Pitx2，Myf5和Pax7之间进行中继，以维持EOM干细胞。我们还证明了EOM中的MuSCs较早采取静止状态，而四肢肌肉中的MuSCs则不会在成虫中自发增殖，然而EOM在产前和产后每个区域的Pax7+MuSCs含量显著较高。最后,而肢体MuSCs在Duchenne肌营养不良mdx小鼠模型中增殖，与对照组相比，mdx小鼠模型的EOM中存在的MuSC显着减少，它们没有增殖。总的来说,我们的研究提供了MuSC沿着身体轴的异质性的全面体内表征,并进一步了解了肌肉营养不良期间EOM的异常保留。
