Cortical synaptogenesis is thought to be initially imprecise and refined over time. We suspect that the final arrangement of CMS synapses is an example of """"""""sorting"""""""" or """"""""reshuffling"""""""" based on specific pre-to- postsynaptic interactions. Via their binding specificity, adhesion molecules are the basis for """"""""sorting"""""""" cells into groups and layers throughout embryonic development and have been thought to function similarly during synaptogenesis as well. Molecules that mediate fine specificity and sorting during synaptogenesis are expected to be differentially expressed in unpredictable combinations in neurons of the same type and from the same lineages. The clustered protocadherins (Pcdhs), novel putative neural adhesion/recognition molecules, exhibit properties expected of molecules that mediate a precise level of synaptic recognition. Their genes are organized into unusual clusters that may reflect the mechanism by which unpredictable combinations of different Pcdhs can be expressed within similar neuronal types. Based on our data and work from others, we hypothesize that the Pcdhs are a basis for a recognition """"""""code"""""""" among neurons by controlling the sorting of intracellular membrane bound synaptic proteins to correctly matched nascent synapses during synaptogenesis resulting in synaptic maturation. We propose two Specific Aims to test our hypothesis.
In Aim 1, we will determine whether Pcdhs are actually adhesion/recognition molecules and characterize their cytoplasmic interactions.
In Aim 2, we will characterize the subcellular trafficking and synaptic insertion processes of the Pcdhs that we suspect underlie Pcdh mediated maturation of correctly matched synapses. Upon completion of these Aims we expect to have a better understanding of the role of cell-cell interactions in synaptogenesis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS051238-05
Application #
7760188
Study Section
Neurodifferentiation, Plasticity, and Regeneration Study Section (NDPR)
Program Officer
Talley, Edmund M
Project Start
2006-08-02
Project End
2012-01-31
Budget Start
2010-02-01
Budget End
2012-01-31
Support Year
5
Fiscal Year
2010
Total Cost
$366,612
Indirect Cost
Name
Icahn School of Medicine at Mount Sinai
Department
Neurosciences
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Phillips, Greg R; LaMassa, Nicole; Nie, Yan Mei (2017) Clustered protocadherin trafficking. Semin Cell Dev Biol 69:131-139
Shonubi, Adam; Roman, Chantelle; Phillips, Greg R (2015) The clustered protocadherin endolysosomal trafficking motif mediates cytoplasmic association. BMC Cell Biol 16:28
Wong, Esther; Bejarano, Eloy; Rakshit, Moumita et al. (2012) Molecular determinants of selective clearance of protein inclusions by autophagy. Nat Commun 3:1240
Reilly, James E; Hanson, Hugo H; Phillips, Greg R (2011) Persistence of excitatory shaft synapses adjacent to newly emerged dendritic protrusions. Mol Cell Neurosci 48:129-36
Reilly, James E; Hanson, Hugo H; Fernandez-Monreal, Monica et al. (2011) Characterization of MSB synapses in dissociated hippocampal culture with simultaneous pre- and postsynaptic live microscopy. PLoS One 6:e26478
O'Leary, Robert; Reilly, James E; Hanson, Hugo H et al. (2011) A variable cytoplasmic domain segment is necessary for ?-protocadherin trafficking and tubulation in the endosome/lysosome pathway. Mol Biol Cell 22:4362-72
Fernández-Monreal, Mónica; Oung, Twethida; Hanson, Hugo H et al. (2010) ?-protocadherins are enriched and transported in specialized vesicles associated with the secretory pathway in neurons. Eur J Neurosci 32:921-31
Schalm, Stefanie S; Ballif, Bryan A; Buchanan, Sean M et al. (2010) Phosphorylation of protocadherin proteins by the receptor tyrosine kinase Ret. Proc Natl Acad Sci U S A 107:13894-9
Fernandez-Monreal, Monica; Oung, Twethida; Hanson, Hugo H et al. (2010) Gamma-protocadherins are enriched and transported in specialized vesicles associated with the secretory pathway in neurons. Eur J Neurosci :
Hanson, Hugo H; Kang, Semie; Fernández-Monreal, Mónica et al. (2010) LC3-dependent intracellular membrane tubules induced by gamma-protocadherins A3 and B2: a role for intraluminal interactions. J Biol Chem 285:20982-92

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