In the past two decades, a great deal of attention has been directed to the study of synaptogenesis in the mammalian central nervous system. Many of these studies are driven by the belief that the diagnosis and the prevention of synapse loss associated with several neurodegenerative diseases can be achieved through a better understanding of the basic mechanisms of synapse formation in central neurons. Although these mechanisms are not completely understood, it is tempting to speculate that proteins, such as agrin, that play a key role in the formation of the neuromuscular junction might also play an important role in the formation of synaptic contacts between neurons. Recently, we have shown that agrin differentially regulates the rates of axonal and dendritic elongation as well as synapse formation in hippocampal neurons. However, the agrin receptor(s) has yet to be identified in these neurons. The experiments proposed here are intended to test the following hypothesis: ror proteins, two tyrosine kinase receptors considered """"""""orphan receptors"""""""", could mediate the effects of agrin on early stages of development in central neurons. A combination of techniques including: Western blot analysis, immunocytochemistry, RT-PCR, the generation of null mutations, binding assays, and immunoprecipitation will be used to analyze: 1) the pattern of expression and localization of ror 1 and ror 2 in central neurons; 2) the role of these tyrosine kinase receptors in neurite elongation and synapse formation; and 3) the participation of ror 1 and ror 2 in the agrin-signaling pathway.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS046834-05
Application #
7214180
Study Section
Molecular, Cellular and Developmental Neurosciences 2 (MDCN)
Program Officer
Mamounas, Laura
Project Start
2003-05-15
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2009-03-31
Support Year
5
Fiscal Year
2007
Total Cost
$234,088
Indirect Cost
Name
Northwestern University at Chicago
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Paganoni, S; Bernstein, J; Ferreira, A (2010) Ror1-Ror2 complexes modulate synapse formation in hippocampal neurons. Neuroscience 165:1261-74
Bergstrom, R A; Sinjoanu, R C; Ferreira, A (2007) Agrin induced morphological and structural changes in growth cones of cultured hippocampal neurons. Neuroscience 149:527-36
Tournell, C E; Bergstrom, R A; Ferreira, A (2006) Progesterone-induced agrin expression in astrocytes modulates glia-neuron interactions leading to synapse formation. Neuroscience 141:1327-38
Loomis, Patricia A; Kelly, Alexander E; Zheng, Lili et al. (2006) Targeted wild-type and jerker espins reveal a novel, WH2-domain-dependent way to make actin bundles in cells. J Cell Sci 119:1655-65
Paganoni, Sabrina; Ferreira, Adriana (2005) Neurite extension in central neurons: a novel role for the receptor tyrosine kinases Ror1 and Ror2. J Cell Sci 118:433-46
Paganoni, Sabrina; Anderson, Kelsi L; Ferreira, Adriana (2004) Differential subcellular localization of Ror tyrosine kinase receptors in cultured astrocytes. Glia 46:456-66
Paganoni, Sabrina; Ferreira, Adriana (2003) Expression and subcellular localization of Ror tyrosine kinase receptors are developmentally regulated in cultured hippocampal neurons. J Neurosci Res 73:429-40