Living organisms are highly efficient and often reuse the same genes multiple times for different purposes. If one function of a gene is essential, death or arrest of the mutant masks other, later functions. This blind spot to later functions of essential genes is particularly troublesome in the nervous system. Most neurons can't be renewed from stem cell populations and therefore must survive and preserve their information- processing capabilities throughout the life of the organism. To accomplish this feat of survival, neurons must maintain their structure and repair it when damaged. But because maintenance and regeneration occur after development, the contribution of essential genes to maintaining and regenerating aging neurons is poorly understood. This project develops a novel strategy in C. elegans for achieving spatial and temporal control of gene inactivation. By using this strategy, it is possible to circumvent the initial requirement for essential genes. Further, the strategy has a critical advantage over existing techniques for making conditional or inducible knockouts: it is compatible with genetic screens. Thus, this strategy breaks down the barrier that prevents genetic screens from finding the later functions of essential genes. This important advance will enable multiple functions of essential genes to be teased apart wherever they occur. This project deploys this strategy to discover the function of essential genes specifically in neurons, focusing on cell survival, development, maintenance of axons and synapses, and regeneration. These experiments should identify a set of common factors that help preserve and restore neural function in all nervous systems, long after development has ended. A hallmark of many neurological diseases is delayed onset. Further, age-related decline in nervous system function occurs even in the absence of known disease. These observations suggest that post-developmental changes in the mature nervous system result in disease susceptibility and loss of function. By inactivating genes in neurons after their development is complete, this project will identify critical functions for conserved genes in aging neurons, with broad relevance for aging, disease susceptibility, and drug target discovery.

Public Health Relevance

As neurons age, they need to maintain their function and structure, and repair themselves when damaged. This project will develop a novel genetic technology for the spatial and temporal regulation of gene inactivation. By inactivating genes in neurons after their development is complete, this project will identify critical functions for conserved genes in aging neurons, with broad relevance for aging, disease susceptibility, and drug target discovery.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS066082-04
Application #
8296525
Study Section
Special Emphasis Panel (ZMH1-ERB-L (05))
Program Officer
Talley, Edmund M
Project Start
2009-07-15
Project End
2013-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$324,380
Indirect Cost
$128,380
Name
Yale University
Department
Genetics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Edwards, Tyson J; Hammarlund, Marc (2014) Syndecan promotes axon regeneration by stabilizing growth cone migration. Cell Rep 8:272-83
Williams, Daniel C; Bejjani, Rachid El; Ramirez, Paula Mugno et al. (2013) Rapid and permanent neuronal inactivation in vivo via subcellular generation of reactive oxygen with the use of KillerRed. Cell Rep 5:553-63
Firnhaber, Christopher; Hammarlund, Marc (2013) Neuron-specific feeding RNAi in C. elegans and its use in a screen for essential genes required for GABA neuron function. PLoS Genet 9:e1003921
Bejjani, Rachid El; Hammarlund, Marc (2012) Notch signaling inhibits axon regeneration. Neuron 73:268-78
Byrne, Alexandra B; Edwards, Tyson J; Hammarlund, Marc (2011) In vivo laser axotomy in C. elegans. J Vis Exp :