Sundararajan Lakshmi, Norris Megan L, Lundquist Erik A
Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045.
Programs in Genetics and Molecular, Cellular, and Developmental Biology, Department of Molecular Biosciences, University of Kansas, Lawrence, Kansas 66045
G3 (Bethesda). 2015 May 28;5(8):1567-74. doi: 10.1534/g3.115.018770.
The Q neuroblasts in Caenorhabditis elegans display left-right asymmetry in their migration, with QR and descendants on the right migrating anteriorly, and QL and descendants on the left migrating posteriorly. Initial QR and QL migration is controlled by the transmembrane receptors UNC-40/DCC, PTP-3/LAR, and the Fat-like cadherin CDH-4. After initial migration, QL responds to an EGL-20/Wnt signal that drives continued posterior migration by activating MAB-5/Hox activity in QL but not QR. QR expresses the transmembrane protein MIG-13, which is repressed by MAB-5 in QL and which drives anterior migration of QR descendants. A screen for new Q descendant AQR and PQR migration mutations identified mig-13 as well as hse-5, the gene encoding the glucuronyl C5-epimerase enzyme, which catalyzes epimerization of glucuronic acid to iduronic acid in the heparan sulfate side chains of heparan sulfate proteoglycans (HSPGs). Of five C. elegans HSPGs, we found that only SDN-1/Syndecan affected Q migrations. sdn-1 mutants showed QR descendant AQR anterior migration defects, and weaker QL descendant PQR migration defects. hse-5 affected initial Q migration, whereas sdn-1 did not. sdn-1 and hse-5 acted redundantly in AQR and PQR migration, but not initial Q migration, suggesting the involvement of other HSPGs in Q migration. Cell-specific expression studies indicated that SDN-1 can act in QR to promote anterior migration. Genetic interactions between sdn-1, mig-13, and mab-5 suggest that MIG-13 and SDN-1 act in parallel to promote anterior AQR migration and that SDN-1 also controls posterior migration. Together, our results indicate previously unappreciated complexity in the role of multiple signaling pathways and inherent left-right asymmetry in the control of Q neuroblast descendant migration.
秀丽隐杆线虫中的Q神经母细胞在迁移过程中表现出左右不对称性，右侧的QR及其后代向前迁移，而左侧的QL及其后代向后迁移。QR和QL的初始迁移受跨膜受体UNC-40/DCC、PTP-3/LAR以及类Fat钙黏蛋白CDH-4控制。初始迁移后，QL对EGL-20/Wnt信号作出反应，该信号通过激活QL而非QR中的MAB-5/Hox活性来驱动持续的向后迁移。QR表达跨膜蛋白MIG-13，其在QL中被MAB-5抑制，并驱动QR后代向前迁移。一项针对新的Q后代AQR和PQR迁移突变的筛选鉴定出了mig-13以及hse-5，hse-5是编码葡萄糖醛酸C5-表异构酶的基因，该酶催化硫酸乙酰肝素蛋白聚糖（HSPG）硫酸乙酰肝素侧链中葡萄糖醛酸向艾杜糖醛酸的表异构化。在秀丽隐杆线虫的五种HSPG中，我们发现只有SDN-1/多配体聚糖影响Q迁移。sdn-1突变体表现出QR后代AQR向前迁移缺陷以及较弱的QL后代PQR迁移缺陷。hse-5影响Q的初始迁移，而sdn-1不影响。sdn-1和hse-5在AQR和PQR迁移中起冗余作用，但在Q的初始迁移中不起作用，这表明其他HSPG参与了Q迁移。细胞特异性表达研究表明，SDN-1可在QR中发挥作用以促进向前迁移。sdn-1、mig-13和mab-5之间的遗传相互作用表明，MIG-13和SDN-1并行发挥作用以促进AQR向前迁移，并且SDN-1还控制向后迁移。总之，我们的结果表明，在多个信号通路的作用以及Q神经母细胞后代迁移控制中固有的左右不对称性方面，存在此前未被认识到的复杂性。
