Coordinating Adhesion Receptors in Axon Growth

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DESCRIPTION (provided by applicant): Retinal ganglion cell axons are guided along their trajectories during development by many different systems of adhesion, attraction and repulsion. Proper axon growth and guidance requires integration in the growth cone of information from many distinct receptor systems. Our long term goals are to identify the environmental cues and signaling paths that integrate adhesion receptor function during development of axons in the neural retina. N-cadherin and beta1-integrins are two of the adhesion systems that play decisive roles in retinal axon elongation and guidance. We have discovered a pathway which coordinately regulates N-cadherin and beta1-integrin function during axon outgrowth. When cells or growth cones contact the chondroitin sulfate proteoglycan neurocan, both N-cadherin and beta1-integrin function is lost. This coordinate loss of function correlates with translocation of the non-receptor tyrosine kinase Fer from its usual association in the cadherin complex of proteins to the complex of proteins associated with the cytoplasmic domain of beta1-integrin. Our hypothesis is that coordinate regulation of cadherin and integrin plays an important role in preventing ganglion cell axons from straying from their appropriate path. The goal of this application is to define the role of Fer in cadherin and integrin function and to examine the role of this pathway in the development of retina ganglion cell axons. Aims 1 and 2 define the role of Fer in the function of cadherin and integrin respectively. We will identify effectors whose presence or phosphorylation is altered in the presence and absence of Fer and how these altered components regulate function. Aim 3 defines the regulatory site in the cadherin cytoplasmic domain responsible for transducing the signal initiating the shuttling of Fer. This will be accomplished by deletion and mutagenesis of N-cadherin, as well as functional comparison of other Type I and II cadherins present in the neural retina for the ability to participate in cross-regulation between cadherin and integrin. In Aim 4 we will determine the role of this cross regulatory circuit in development of retinal ganglion cell axon projections through inhibition of the binding of neurocan, the extracellular signal that initiates coordinate regulation, and through the use of cell permeable peptides to perturb cadherin and/or integrin function.