The Rac GTP Exchange Factor TIAM-1 Acts with CDC-42 and the Guidance Receptor UNC-40/DCC in Neuronal Protrusion and Axon Guidance
The Rac GTP Exchange Factor TIAM-1 Acts with CDC-42 and the Guidance Receptor UNC-40/DCC in Neuronal Protrusion and Axon Guidance
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DOI：
10.1371/journal.pgen.1002665
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发表时间：
2012-04-01
期刊：
影响因子：
4.5
通讯作者：
Lundquist, Erik A.
中科院分区：
文献类型：
--
作者：
Demarco, Rafael S.;Struckhoff, Eric C.;Lundquist, Erik A.
在轴突延伸过程中，生长锥中引导受体与细胞骨架动力学的联系机制仍然是一个谜。rho家族GTPases Rac和CDC-42是生长锥板足和丝状足形成的关键调节因子，但对于这些分子如何在生长锥的生长中相互作用，以及这些分子的活性如何在不同的环境中被调节，人们知之甚少。UNC-73/Trio是秀丽隐杆线虫轴突寻路中表征良好的Rac GTP交换因子，但UNC-73在吸引轴突引导中不控制UNC-6/Netrin下游的ce -10/Rac。本研究表明秀丽隐杆线虫TIAM-1是一个Rac特异性的GEF，在UNC-40/DCC下游板足和丝足形成过程中连接CDC-42和Rac信号。我们还发现TIAM-1与UNC-40/DCC在轴突引导中起作用。我们的研究结果表明，CDC-42/TIAM-1/Rac GTPase信号通路驱动UNC-40/DCC引导受体下游的板足和丝足形成，这是这些分子之间的一组新的相互作用。此外，我们发现TIAM-1在轴突引导中与UNC-40/DCC一起作用，表明TIAM-1可能通过Rac GTPases响应UNC-40/DCC调节生长锥突。我们的研究结果还表明，Rac GTPase活性在不同的轴突引导背景下由不同的gef控制，这解释了Rac GTPase如何特异性地控制多种细胞功能。
The mechanisms linking guidance receptors to cytoskeletal dynamics in the growth cone during axon extension remain mysterious. The Rho-family GTPases Rac and CDC-42 are key regulators of growth cone lamellipodia and filopodia formation, yet little is understood about how these molecules interact in growth cone outgrowth or how the activities of these molecules are regulated in distinct contexts. UNC-73/Trio is a well-characterized Rac GTP exchange factor in Caenorhabditis elegans axon pathfinding, yet UNC-73 does not control CED-10/Rac downstream of UNC-6/Netrin in attractive axon guidance. Here we show that C. elegans TIAM-1 is a Rac-specific GEF that links CDC-42 and Rac signaling in lamellipodia and filopodia formation downstream of UNC-40/DCC. We also show that TIAM-1 acts with UNC-40/DCC in axon guidance. Our results indicate that a CDC-42/TIAM-1/Rac GTPase signaling pathway drives lamellipodia and filopodia formation downstream of the UNC-40/DCC guidance receptor, a novel set of interactions between these molecules. Furthermore, we show that TIAM-1 acts with UNC-40/DCC in axon guidance, suggesting that TIAM-1 might regulate growth cone protrusion via Rac GTPases in response to UNC-40/DCC. Our results also suggest that Rac GTPase activity is controlled by different GEFs in distinct axon guidance contexts explaining how Rac GTPases can specifically control multiple cellular functions.