The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons
The requirement for Phr1 in CNS axon tract formation reveals the corticostriatal boundary as a choice point for cortical axons
复制标题
DOI：
10.1101/gad.1592107
复制
发表时间：
2007-10-15
影响因子：
10.5
通讯作者：
DiAntonio, Aaron
中科院分区：
文献类型：
--
作者：
Bloom, A. Joseph;Miller, Bradley R.;DiAntonio, Aaron
Phr 1是无脊椎动物泛素连接酶基因highwire（果蝇）和rpm-1（秀丽隐杆线虫）的单一高度保守的小鼠直系同源物。highwire和rpm-1的功能和作用机制是相似的，都是通过下调丝裂原活化蛋白激酶双亮氨酸拉链激酶（MAPKKK DLK）的直系同源物来自主调节突触发生。在这里，使用有针对性的条件突变体，我们表明，Phr 1在哺乳动物神经发育中也发挥着重要作用。在无脊椎动物中，Phr 1的功能是细胞自主地塑造运动神经末梢。此外，Phr 1在主要CNS轴突束的形成中起着至关重要的作用，包括内囊的轴突束，部分通过细胞非自主机制，这些结果揭示了皮质轴突在皮质纹状体边界的选择点。此外，而highwire和rpm-1的神经突形态表型被抑制的损失DLK在苍蝇和蠕虫，Phr 1依赖的中枢神经系统缺陷持续Phr 1，DLK双突变体。因此，在哺乳动物神经系统中，Phr 1是通过细胞非自主和独立于DLK的机制形成主要CNS轴突束所必需的。
Phr1 is the single well-conserved murine ortholog of the invertebrate ubiquitin ligase genes highwire ( in Drosophila) and rpm-1 ( in Caenorhabditis elegans). The function and mechanism of action of highwire and rpm-1 are similar-both cell-autonomously regulate synaptogenesis by down-regulating the ortholog of the mitogen-activated protein kinase kinase kinase dual leucine zipper kinase ( MAPKKK DLK). Here, using a targeted conditional mutant, we demonstrate that Phr1 also plays essential roles in mammalian neural development. As in invertebrates, Phr1 functions cell-autonomously to sculpt motor nerve terminals. In addition, Phr1 plays essential roles in the formation of major CNS axon tracts including those of the internal capsule, in part via cell-nonautonomous mechanisms, and these results reveal a choice point for cortical axons at the corticostriatal boundary. Furthermore, whereas the neurite morphology phenotypes of highwire and rpm-1 are suppressed by loss of DLK in flies and worms, Phr1-dependent CNS defects persist in Phr1, DLK double mutants. Thus, in the mammalian nervous system Phr1 is required for formation of major CNS axon tracts via a mechanism that is both cell-nonautonomous and independent of DLK.