Homer in Axon Pathfinding

Abstract

Homer family proteins function as intracellular adapter proteins and are composed of well-characterized protein domains. In mammals, Homer1 is alternatively spliced to produce three different proteins: Homer1a, 1b, and 1c. All three isoforms have an EVH1 (enabled VASP homology 1) domain that allows Homer proteins to associate with other proteins that contain specific proline-rich motifs. However, only the longer forms of Homer (1b and 1c) have a COOH-terminal coiled-coil domain that allows Homer proteins to dimerize. Foa et al. expressed Homer1 proteins in Xenopus and determined that Homer1 proteins have an essential role in axon pathfinding. Overexpression of vaccinia virus-transduced Homer1a led to the development of aberrant axonal projections and incorrect pathfinding in Xenopus optical tecta. Expression of a Homer1a mutant that prevented protein binding did not interfere with pathfinding, suggesting that Homer1a was interfering possibly with the ability of Homer1b/1c to cross-link proteins important for pathfinding. Overexpression of a Homer1c mutant that could dimerize but not bind other proteins also resulted in defective pathfinding, probably as a result of being unable to recruit and cross-link essential proteins necessary for pathfinding. Overexpression of wild-type Homer1c also resulted in defective axonal pathfinding; however, this might be explained by the possibility that high nonphysiological amounts of Homer1c dimerize before binding the critical transmembrane proteins. In this instance, the transmembrane proteins would be occupied and unavailable for cross-linking, thus leading to the outcome of defective axonal pathfinding. L. Foa, I. Rajan, K. Haas, G.-Y. Wu, P. Brakeman, P. Worley, H. Cline, The scaffold protein, Homer1b/c, regulates axon pathfinding in the central nervous system in vivo. Nature Neurosci. 4, 499-506 (2001).[Online Journal]