不同的Rac活化路徑控制線蟲的神經細胞遷移和軸突生長

Abstract

Rac GTPases的功能和細胞骨骼重組有關，在許多發育過程中扮演關鍵性的角色；然而在多細胞生物體發育過程中如何調控這些分子的活性卻不是非常清楚。ced-10和mig-2是線蟲的兩個Rac GTPases。較強的ced-10突變會造成蟲體運動不協調；mig-2 null mutation的突變株運動正常，整體影響不大。為了進一步暸解ced-10和mig-2在神經細胞發育過程中所扮演的角色和上游分子的調控機制，我們以遺傳學方法分析ced-10和mig-2在特定感覺和運動神經元發育過程中的功能。 我們發現ced-10和mig-2是兩條獨立的訊息傳導路裡，共同控制P細胞遷移以及D型運動神經元的軸突生長。這兩個 Rac GTPases也共同控制amphid感覺神經元的軸突生長，但amphid樹突的形成卻不需要ced-10和mig-2的參與。實驗結果顯示在P細胞遷移以及D型運動神經元和amphid感覺神經元軸突生長過程中，unc-73這個Trio-like guanine nucleotide exchange factor (GEF)可活化ced-10和mig-2，作為它們共同的GEF。此外作用在ced-10上游來控制 DTC細胞遷移和死細胞吞噬的rac調控因數：ced-2/Crkll和ced-5/DOCK180，在D型運動神經元軸突生長時作用在 ced-10和mig-2上游，P細胞遷移時則只作用在mig-2上游。然而在amphid感覺神經元軸突生成時，ced-2和ced-5都不參與其中。由此可知：在各種細胞的發育過程中，不同的rac上游調控因數以各種不同的方式來調控ced-10和 mig-2的活性。

Rac GTPases are involved in cytoskeletal rearrangement and act as molecular switch in various morphogenic events. However, the regulation of their activities during the development of multicellular organisms is not well understood. ced-10 and mig-2 are members of Rac GTPase family in C.elegans. A strong ced-10 mutation causes the uncoordinated phenotype while the null mutation in mig-2 does not have a strong influence in neuronal development in general. To understand roles of ced-10 and mig-2 and identify their respective upstream regulators during neuronal development we have undertaken genetic approaches and analyzed their functions in the development of specific motor and sensory neurons. We showed that ced-10 and mig-2 act redundantly to control P cell migration and the axon outgrowth of D type motoneurons. These two Rac GTPases also control amphid axon outgrowth in a redundant fashion but their activities are not required for the amphid dendrite formation. Our genetic data indicate that unc-73, which encodes a protein related to Trio-like guanine nucleotide exchange factor, acts as an activator of ced-10 and mig-2 during P cell migration and axon outgrowth of D type motoneurons and amphid sensory neurons. Furthermore, rac regulators ced-2/crkll and ced-5/dock180 that function upstream of ced-10 during DTC migration and cell-corpse engulfment act genetically upstream of ced-10 and mig-2 during axon outgrowth of D-type motor neurons and appear to act on mig-2 rather than ced-10 during P cell migration. However, neither ced-2/crkll nor ced-5/dock180 is involved in amphid axon outgrowth. Therefore, distinct rac regulators control ced-10 and mig-2 differentially in various cellular processes.