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Updated: Nov 5, 2025
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Published on: November 29, 2016
Parallel Rap1>RalGEF>Ral and Ras signals sculpt the C. elegans nervous system
Jacob I Mardick1, Neal R Rasmussen1, Bruce Wightman2
1Department of Translational Medical Science, College of Medicine, Texas A&M Universsity, Houston, TX, USA; Institute of Biosciences and Technology, Texas A&M Health Science Center, Texas A&M University, Houston, TX, USA.
Abstract:
Ras is the most commonly mutated oncogene in humans and uses three oncogenic effectors: Raf, PI3K, and RalGEF activation of Ral. Understanding the importance of RalGEF>Ral signaling in cancer is hampered by the paucity of knowledge about their function in animal development, particularly in cell movements. We found that mutations that disrupt function of RalGEF or Ral enhance migration phenotypes of mutants for genes with established roles in cell migration. We used as a model the migration of the canal associated neurons (CANs), and validated our results in HSN cell migration, neurite guidance, and general animal locomotion. These functions of RalGEF and Ral are specific to their control of Ral signaling output rather than other published functions of these proteins. In this capacity Ral functions cell autonomously as a permissive developmental signal. In contrast, we observed Ras, the canonical activator of RalGEF>Ral signaling in cancer, to function as an instructive signal. Furthermore, we unexpectedly identified a function for the close Ras relative, Rap1, consistent with activation of RalGEF>Ral. These studies define functions of RalGEF>Ral, Rap1 and Ras signaling in morphogenetic processes that fashion the nervous system. We have also defined a model for studying how small GTPases partner with downstream effectors. Taken together, this analysis defines novel molecules and relationships in signaling networks that control cell movements during development of the nervous system.
Insights
Ras signaling pathways are crucial in cancer. This study reveals RalGEF-Ral signaling
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Biology
Background:
- Ras is a key human oncogene, with RalGEF-Ral signaling being a critical effector pathway.
- Understanding RalGEF-Ral signaling in development and cancer is limited, particularly regarding cell migration.
- Small GTPases and their downstream effectors play vital roles in cellular processes.
Purpose of the Study:
- To investigate the role of RalGEF-Ral signaling in animal development, specifically in cell migration.
- To elucidate the distinct functions of Ras and Rap1 in RalGEF-Ral pathway activation.
- To establish a model for studying small GTPase interactions with downstream effectors in developmental contexts.
Main Methods:
- Utilized genetic mutations disrupting RalGEF or Ral function in model organisms.
- Examined phenotypes in canal associated neuron (CAN) migration, HSN cell migration, neurite guidance, and animal locomotion.
- Compared the signaling functions of Ras and Rap1 in activating the RalGEF-Ral pathway.
Main Results:
- Disruptions in RalGEF or Ral function exacerbated cell migration defects in established mutants.
- RalGEF-Ral signaling acts as a cell-autonomous permissive signal, distinct from Ras's instructive role.
- Rap1 was identified to function through RalGEF-Ral activation, similar to Ras.
Conclusions:
- RalGEF-Ral signaling is essential for nervous system development and cell movements.
- Ras and Rap1 exhibit distinct modes of activation for the RalGEF-Ral pathway.
- This study provides novel insights into small GTPase signaling networks controlling developmental morphogenetic processes.
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