Abstract

During development, molecules in the immature brain steer axons to their target areas, following long and complex pathways. Proper pathfinding is required for the establishment of correct synaptic connections, and disturbances in the intricately regulated process of axonal pathfinding are thought to cause a variety of neurodevelopmental disorders. Netrin-1 is a secreted, attractive axon guidance cue that is crucial for the proper formation of the nervous system. The mechanisms by which netrin-1 mediates its axon outgrowth promoting effects are largely unknown, and the pathways identified thus far seem incongruent: cAMP/PKA signaling, intra-axonal protein synthesis and degradation, and regulation of the activity of Rho family GTPases, proteins with l The specific aims of this proposal are designed to validate this model and to determine the importance of local PARS translation in an in vivo model. As part of a long-term effort to understand how molecules such as netrin-1 regulate axonal outgrowth and pathfinding, the aims of this proposal are: (I) To demonstrate the role of Smurfl-dependent ubiquitination of RhoA in netrin-1 signaling, (II) to establish the role of local translation of PARS in netrin-1 signaling, and (III) to genetically dissect the role of axonally localized PARS mRNA in axon pathfinding in vivo. The results obtained from these experiments will create the foundation for a novel and unified framework for understanding netrin-1 signaling.

Public Health Relevance

During development, guidance molecules in the immature brain direct axons to their target areas; disturbances in this process cause neurodevelopmental disorders, such as schizophrenia. This proposal addresses the intra-axonal mechanisms governing this process. I expect my studies to have broad relevance for the understanding of the aetiology of neurodevelopmental disorders.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Transition Award (R00)
Project #
5R00MH081058-04
Application #
7938782
Study Section
Special Emphasis Panel (NSS)
Program Officer
Panchision, David M
Project Start
2007-07-30
Project End
2012-06-30
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
4
Fiscal Year
2010
Total Cost
$242,476
Indirect Cost

  Institution

Name
Columbia University (N.Y.)
Department
Pathology
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032

  Publications

Deglincerti, Alessia; Liu, Yaobin; Colak, Dilek et al. (2015) Coupled local translation and degradation regulate growth cone collapse. Nat Commun 6:6888
Gracias, Neilia G; Shirkey-Son, Nicole J; Hengst, Ulrich (2014) Local translation of TC10 is required for membrane expansion during axon outgrowth. Nat Commun 5:3506
Hengst, Ulrich; Deglincerti, Alessia; Kim, Hyung Joon et al. (2009) Axonal elongation triggered by stimulus-induced local translation of a polarity complex protein. Nat Cell Biol 11:1024-30