Experimental Sey mouse chimeras reveal the developmental deficiencies of Pax6-null granule cells in the postnatal cerebellum.
Experimental Sey mouse chimeras reveal the developmental deficiencies of Pax6-null granule cells in the postnatal cerebellum.
复制标题
DOI：
10.1016/j.ydbio.2010.11.018
复制
发表时间：
2011-03
影响因子：
2.7
通讯作者：
D. Swanson;D. Goldowitz
中科院分区：
文献类型：
--
作者：
D. Swanson;D. Goldowitz
Pax6与小脑颗粒细胞发育有关，然而，Sey/Sey突变体的新生儿致死率阻碍了对这种晚期发育神经元类型的更详细研究。在这项研究中，我们使用野生型和pax6缺失胚胎制成的实验性小鼠嵌合体来规避早期致死并评估突变细胞在小脑构建中的发育潜力。我们已经确定颗粒细胞是突变基因作用的直接靶点，胶质细胞和浦肯野细胞在很大程度上以非细胞自主的方式受到影响。最引人注目的是，在出生后21天（P21）的嵌合体中，突变细胞在小脑前部和后部大部分不存在，而在中央小叶中存在，但在紊乱的小脑结构中存在。对P0/1和P10嵌合体的分析表明，突变细胞在EGL的前部和后部定殖，但不能迁移到IGL，这是一种深刻的基于时间的缺陷。中央小叶的突变颗粒细胞可以异常方式到达IGL，大量细胞流通过分子层形成图形。这些研究为Pax6在出生后小脑发育中的作用提供了新的见解，指出颗粒细胞是突变基因的内在靶点，以及依赖于Pax6正常表达的发育颗粒细胞生命中的关键事件。
Pax6 has been implicated in cerebellar granule cell development, however the neonatal lethality of the Sey/Sey mutant has precluded a more detailed study of this late developing neuronal type. In this study we use experimental mouse chimeras made from wildtype and Pax6-null embryos to circumvent early lethality and assess the developmental potential of mutant cells in the construction of the cerebellum. We have identified the granule cell as a direct target of mutant gene action, with glia and Purkinje cells being affected in what is largely a non-cell autonomous manner. Most dramatically, in postnatal day 21 (P21) chimeras, mutant cells are largely absent in the anterior and posterior cerebellum while present in central lobules, but amidst disorganized cerebellar architecture. Analysis of P0/1 and P10 chimeras demonstrates a profound temporally based defect where mutant cells colonize the anterior and posterior EGL but fail to migrate to the IGL. Mutant granule cells in the central lobules can reach the IGL in an abnormal manner, with large streams of cells forming raphes through the molecular layer. These studies provide new insights into the role of Pax6 in postnatal cerebellar development that pinpoint the granule cell as an intrinsic target of the mutant gene and key events in the life of the developing granule cell that depend upon normal Pax6 expression.