Salk Institute for Biological Studies


John B. Thomas

John B. Thomas

Molecular Neurobiology Laboratory



The focus of our research is to understand how neurons are assembled during development to produce a functioning nervous system. The growth cones at the tips of developing axons are guided to their synaptic target cells by cues in the extracellular environment. Specific receptors on the growth cones recognize these cues and transduce signals that ultimately lead to changes in direction of growth. To identify these guidance molecules, we have taken a genetic approach in Drosophila by isolating mutations that alter specific features of axon guidance and target recognition. For our mutant screens we created a set of axon-targeted reporters that allow us to directly visualize the morphology of neurons expressing them. Our screens have yielded a number of molecules, from axon guidance receptors such as Derailed, which together with its ligand Wnt5, controls how axons project across the midline, to a family of transcription factors, the LIM-homeodomain proteins, which combinatorially control motor neuron pathway selection and muscle target recognition. The guidance molecules we have discovered in Drosophila have mammalian homologs that turn out also to function in axon guidance.

From the work of our lab and a number of others we know something about how axons are guided to their target destinations in order to eventually synapse with their appropriate target cells, thus forming the neural circuits that make up the nervous system. However, we have little understanding of how these circuits are actually assembled. We know even less about how they generate behaviors. To begin addressing these questions, we are functionally and anatomically defining neural circuits underlying "simple" behaviors such as locomotion. Our long-term goal is to understand how these circuits develop and function.

"Our long-term goal is to understand how nerve cells are assembled into circuits during development to produce a functional nervous system."

Nervous systems generate behaviors through the coordinated activity of specific neural circuits. During development, these circuits are formed by growing nerve cells extending long projections called axons, which hook up with other nerve cells or with muscles to control locomotion. At the tip of each growing axon is the growth cone, which steers the axon to its target cells by responding to cues in the extracellular environment. Capitalizing on our advanced knowledge on the genetics of the fruit fly Drosophila, Thomas's lab has identified key molecules in the axon's navigation system that govern basic events common to all nervous systems, such as axons growing from one side of the brain to the other or projecting out of the nervous system to connect with muscles.

Crosstalk between the two sides of the nervous system is essential for many behaviors, from simple coordinated locomotion to the integration of higher cognitive functions. Its importance is underscored by the large number of nerve cells that project their axons across the midline to the opposite side. Thomas has identified a number of axon guidance molecules, including receptors on the growth cone that bind to specific ligands in the extracellular environment, guiding axons along specific routes across the midline. These receptors and ligands belong to larger families of related molecules that have also been found to guide axons in mammals. This means these guidance molecules are deeply rooted in who we are, whether we are a fly on the wall or a human being wielding a flyswatter.

Once the neural circuits are formed during development using the axon guidance molecules, how do they generate behaviors? The Thomas lab activates and inactivates specific nerve cells to understand the circuit that generates locomotion. Just like the axon guidance molecules, the principles of how circuits generate locomotion in flies will be important to understanding the neural basis of locomotion in higher vertebrates, including humans.

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