The development of the nervous system requires the proper differentiation, migration, morphogenesis andmaturation of neurons. The morphological differentiation of individual neurons and assembly of the trillions ofneuronal connections that compose the human nervous system occurs through guided extension of axons anddendrites. The long-term objective of our research is to better understand the intracellular signaling cascadesand effector mechanisms that are responsible for axon outgrowth and guidance in the developing brain. Forthis we must understand how nerve growth cones detect, integrate and respond to soluble, as well as cell- andsubstratum-associated guidance molecules in their environment. Mutations in genes involved in the detectionand transduction of axon guidance information into directed neurite outgrowth are responsible for many neuro-developmental disorders, including autisms, dyslexias, psychological disorders and cognitive deficits.Therefore, our work aimed at better understanding the molecular basis of normal neural development, mayhelp inform treatments for conditions leading to abnormal neural network assembly.While extensive studies have investigated the molecular mechanisms that regulate axon guidance over two-dimensional substrata in vitro or along axonal tracks in vivo, little is known about the signals that control axonguidance across three-dimensional tissues. Our preliminary and recently published data suggest that alongwith planar filopodia and lamellipodia, growth cones generate orthogonal protrusions in vitro and in vivo thatresemble podosomes or invadopodia. Podosomes and invadopodia, collectively referred to asinvadosomes, are actin-based cellular protrusions associated with extracellular matrix (ECM) degradation andtissue invasion. We hypothesize that growth cone invadosomes function to actively detect ligands throughreceptor interactions that regulate actin polymerization and participate in ligand and receptor degradation tomodulate ligand-mediated guidance. The three aims of this proposal will use a series of molecular gain offunction and loss of function manipulations, together with super resolution three-dimensional fluorescenceimaging, to assess the signals that control invadosome formation and their roles in controlling neural networkformation.
The development of a functional nervous system requires precise guidance of axons and dendrites to theirtarget locations and establishment of proper synaptic connections. This proposal is focused on understandingthe role of invadopodia-like protrusions from growth cones in the regulation of axon guidance through three-dimensional space. The aims of this study will identify the molecular mechanisms the control invadosomeformation and test the role of invadosomes in axon guidance in vitro and in vivo.
| Eno, Celeste; Gomez, Timothy; Slusarski, Diane C et al. (2018) Slow calcium waves mediate furrow microtubule reorganization and germ plasm compaction in the early zebrafish embryo. Development 145: |
| Kerstein, Patrick C; Patel, Kevin M; Gomez, Timothy M (2017) Calpain-Mediated Proteolysis of Talin and FAK Regulates Adhesion Dynamics Necessary for Axon Guidance. J Neurosci 37:1568-1580 |
| Short, Caitlin A; Suarez-Zayas, Edwin A; Gomez, Timothy M (2016) Cell adhesion and invasion mechanisms that guide developing axons. Curr Opin Neurobiol 39:77-85 |
| Catlett, Timothy S; Gomez, Timothy M (2016) Division of labor in the growth cone by DSCR1. J Cell Biol 213:407-9 |
| Nichol IV, Robert H; Hagen, Kate M; Lumbard, Derek C et al. (2016) Guidance of Axons by Local Coupling of Retrograde Flow to Point Contact Adhesions. J Neurosci 36:2267-82 |
