Research Overview
The guided growth of neurons in the developing nervous system is essential to the establishment of synaptic connections, the hallmark of a functional, integrated nervous system. During axon growth, cell-surface adhesion receptors play an essential role in both the recognition of molecular cues in the neuronal environment and the transduction of cellular forces necessary for axon extension. The ability of neurons to generate traction forces depends critically on bonds between adhesion receptors and the cytoskeleton. However, for guided growth to occur, force generation must be oriented with respect to the direction of cell movement. The organized regulation of adhesion receptor-cytoskeleton interactions across the surface is therefore, essential to the both to guided neuronal growth and to the migration of adherent cells in general.
To understand better the regulation of adhesion receptor function in cell migration, we have focused on the neuronal adhesion receptor L1-CAM, a member of the immunoglobulin superfamily. L1-CAM plays an essential role in the guidance of axons in the developing vertebrate central nervous system: mice deficient in L1 show defects in the guidance of specific cortico-spinal axon tracts. Mutations in the Human L1-CAM gene lead to severe mental retardation, consistent with a role for L1-CAM in nervous system function. L1-CAM is a trans membrane glycoprotein that is comprised of 6 amino-terminal Ig domains followed by 5 fibronectin type III repeats outside the cell. Inside the cell, the L1-CAM binds to components of the actin cytoskeleton permitting the generation of organized traction forces at the front of the cell.
Our work is directed at understanding the regulation of L1-CAM-mediated traction force generation in the process of neuronal growth. To address this question we are employing a number of distinct biophysical techniques to identify the interactions mediated by the L1-CAM cytoplasmic tail and to characterize the signaling pathways that regulate these interactions. Our current data suggest that L1-CAM interacts with multiple binding partners in the cytoskeleton, permitting L1-CAM to mediate both neuronal growth and static adhesion. By selectively blocking these interactions with inhibitory peptides, we are able to stimulate or inhibit L1-CAM meditated neuronal growth in vitro . Work currently underway is directed at identifying the second messenger pathways that regulate L1-CAM interactions with the cytoskeleton, information that is crucial for understanding the integration of multiple guidance signals during neuronal development. Knowledge gained from the study of L1-CAM function may also shed new light on other processes that depend on cell migration, including the metastasis of tumors cells during the progression of cancer.