This project investigates the roles of integrin during axon navigation in vivo. A major challenge in neuroscience today is to explain the genetic porgrams that direct development of the brain. The brain is composed of multi-layered networks of neurons that self-organize specific connections. How does a neuronal growth cone communicate with other cells while choosing specific pathways? What molecules are there to mediate such cell recognition and migration? The prevailing view is that accurate axon guidance relies on the activation of cell surface receptors that translate extrinsic cues into directed cytoskeletal rearrangement within a growth cone. Integrin is a family of multi-functional cell surface receptor/adhesion molecules, enriched in axonal growth cones. Although it has been proposed to play unique and important roles during migration and network formation of neurons, the main functions of integrin during axon navigation are not well understood in vivo. Drosophila offers both genetic and cell biological advantages. We apply our lab's expertise and examine the axon navigation defects in integrin knock out mutants, determine the cell autonomous requirement of integrin in axons and begin characterizing how integrin works inside a growth cone in situ. Specific hypotheses will be evaluated in real life contexts (in situ).
Aim 1 evaluates both """"""""speed controller"""""""" and """"""""decision mediator"""""""" models for integrin's roles during axon navigation. It also tests the idea that much of axon defects in knock out mutants reflect integrin's """"""""cell autonomy"""""""" inside neurons that express integrin.
Aim 2 looks inside axons and begins to evaluate the idea that integrin works through forming """"""""focal adhesions"""""""" and/or """"""""filopodia enrichment."""""""" It also examined the differences between alphaPS1 and alphaPS2 knock out phenotypes and ask whether the differences owe to their """"""""expression-based distinctions"""""""" or """"""""structure-based distinctions."""""""" Whereas Aim 1 establishes cellular contexts in which Integrin's in vivo roles can be studied during axon navigation, Aim 2 explores into the molecule-level experimentation in the same in vivo contexts. Thus, the project """"""""bridges"""""""" the gap between the wealth of in vitro (molecule-level) knowledge and the absence of in vivo (cell-level) analysis of integrin. Through this project, we move from the question of """"""""what is integrin capable of doing?"""""""" to that of """"""""what is integrin really doing"""""""" in real life contexts in situ.
| Furrer, Marie-Pierre; Kim, Susan; Wolf, Brian et al. (2003) Robo and Frazzled/DCC mediate dendritic guidance at the CNS midline. Nat Neurosci 6:223-30 |
| Ritzenthaler, Sarah; Chiba, Akira (2003) Myopodia (postsynaptic filopodia) participate in synaptic target recognition. J Neurobiol 55:31-40 |
| Kim, Michael D; Kamiyama, Daichi; Kolodziej, Peter et al. (2003) Isolation of Rho GTPase effector pathways during axon development. Dev Biol 262:282-93 |
| Kim, Michael D; Kolodziej, Peter; Chiba, Akira (2002) Growth cone pathfinding and filopodial dynamics are mediated separately by Cdc42 activation. J Neurosci 22:1794-806 |
