Selective cell-cell interactions are required to establish the precise three-dimensional architecture of the vertebrate nervous system through coordinated cell movements, regional partitioning, axon targeting and synapse formation. The cadherin superfamily comprises a large, diverse array of cell surface receptors that includes both the classical cadherins and the protocadherins. Both classical cadherins and protocadherins have been proposed to play roles in establishing neural circuitry in the developing brain. While the classical cadherins are known to be homophilic cell adhesion molecules, the involvement of protocadherins in cell adhesion remains uncertain. In our previous work, we showed that Protocadherin-19 (Pcdh19) associates with N-cadherin (Ncad) to form a heteromeric cis-complex. In preliminary data, we show that Pcdh19 mediates homophilic adhesion as part of the Pcdh19-Ncad complex, although it is not adhesive itself. The main hypothesis of this proposal is that protocadherins associate with classical cadherins to form cis-complexes with distinct adhesive properties. To investigate this hypothesis in more detail we propose the following Specific Aims.
In Aim 1, we will test the hypothesis that members of the d-protocadherin family form cis-complexes with classical cadherins and determine whether these complexes mediate homophilic adhesion, as we have shown for Pcdh19-Ncad.
In Aim 2, we will first determine the residues in Pcdh19 that constitute the adhesive interface, and then determine if this mechanism is general to Pcdh-Cdh complexes. Insights gained from these experiments will elucidate the molecular underpinnings of a novel mechanism of cell adhesion and will advance our knowledge of protocadherin and cadherin function, providing an essential foundation for understanding the roles of these molecules in neural development and elucidating the mechanisms that establish patterns of neural connectivity.

Public Health Relevance

Protocadherins and cadherins have been implicated in a number of neurodevelopment disorders, including autism, schizophrenia, epilepsy and mental retardation. Despite the importance of protocadherins to neural development, very little is known about their molecular and cellular functions or developmental roles. Our studies will dramatically advance our knowledge of the mechanism of cell adhesion by the protocadherins and provide a foundation for understanding their roles in the development of the vertebrate nervous system.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21MH098463-01
Application #
8359953
Study Section
Intercellular Interactions (ICI)
Program Officer
Asanuma, Chiiko
Project Start
2012-05-24
Project End
2014-04-30
Budget Start
2012-05-24
Budget End
2013-04-30
Support Year
1
Fiscal Year
2012
Total Cost
$228,750
Indirect Cost
$78,750
Name
Ohio State University
Department
Neurosciences
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Emond, Michelle R; Jontes, James D (2014) Bead aggregation assays for the characterization of putative cell adhesion molecules. J Vis Exp :e51762