Axon Guidance and Synaptic Development
- The establishment of precisely wired neuronal networks between the approximately
one-hundred billion neurons in the CNS presents a tremendous challenge for mammalian development. During ontogeny, newly generated neurons must migrate
to their appropriate location within the brain. As they reach their final destination, these cells extend axons and form synapses onto their
targets to generate appropriate neuronal circuits. Each of these steps depends on the ability of neurons to respond to a complex set of
environmental cues and modify their intrinsic maturation program. Over the last decade, significant progress has been made in identifying
both the extracellular factors and neuronal receptors that regulate neuronal development. Neurons and their growth cones respond to these
guidance factors through the coordinated regulation of a variety of intracellular processes including endocytosis, protein and lipid transport,
actin cytoskeletal remodeling, the modulation of microtubule dynamics, and protein synthesis and degradation. A key, unresolved issue is
how cell surface receptors promote these diverse cellular processes to elicit specific cellular responses such as neuronal migration, growth
cone guidance and synapse formation.
To begin to address this question, we have focused on repulsive signaling through the Eph family of receptor tyrosine kinases. The Ephs recognize membrane-bound ephrin ligands displayed on the surface of neighboring cells. Gene knockout experiments have demonstrated a role for ephrin-Eph signaling in the pathfinding of axons, including axons of the corticospinal tract, the corpus callosum, and the anterior commissure, as well as retinotectal map formation, motor axon projections to the periphery, and thalamocortical projections. However, the mechanisms by which downstream signaling molecules mediate Eph signaling in the neuronal growth cone remain largely uncharacterized.
Several years ago we initiated an investigation of the signaling mechanisms by which the Ephs mediate cellular responses during axon guidance. These studies have identified two Dbl family guanine nucleotide exchange factors (GEFs), ephexin1 and Vav2, that associate with the cytoplasmic tail of activated Ephs. Ephexin1 becomes phosphorylated on a critical tyrosine residue in response to EphA signaling in neurons. This phosphorylation event acts to switch ephexin's substrate preference for downstream Rho family GTPases, enhancing RhoA activity and thereby promoting cytoskeletal disassembly. Consistent with these findings, ephexin1-deficient neurons show significant defects in ephrin-induced growth cone collapse. By contrast, Vav proteins appear to mediate the internalization of the ephrin-Eph ligand-receptor complex. In Vav-deficient neurons endocytosis of the ephrin-Eph complex is blocked, leading to defects in ephrin-induced growth cone collapse in vitro and marked defects in the ipsilateral retinogeniculate projections in vivo. Thus, our findings suggest that Ephs promote growth cone repulsion by orchestrating a series of distinct events, and that activated Ephs engage different GEFs to affect the distinct cytoskeletal changes necessary for repulsion.
Shamah SM, Lin MZ, Goldberg JL, Estrach S, Sahin M, Hu L, Bazalakova M, Neve RL, Corfas G, Debant A, Greenberg ME. EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor Ephexin. Cell 2001; 105(2):233-244.
Sahin M, Greer PL, Lin MZ, Poucher H, Eberhart J, Schmidt S, Wright TM, Shamah SM, O'Connell S, Cowan CW, Hu L, Goldberg JL, Debant A, Corfas G, Krull CE, Greenberg ME. Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron, 2005, in press.
Cowan, CW, Shao YR, Sahin M, Shamah SM, Lin MZ, Greer PL, Gao S, Griffith EC, Brugge JS, Greenberg ME. Vav family GEFs link activated Ephs to endocytosis and axon guidance. Neuron, 2005, in press.
Other research areas:
Activity-Dependent Gene Transcription
Regulation of Translation in Neurons
Neuronal Cell Fate Determination
Neuronal Survival and Apoptosis
Synapse Formation and Maintenance
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