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John B. Thomas

 

John B. Thomas

John B. Thomas

Professor
Molecular Neurobiology Laboratory

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

Growing nerve cells are great communicators, extending long projections called axons, which hook up with other specific nerve cells to form functional circuits within the developing nervous system. 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 the advanced genetics of the fruit fly Drosophila, John Thomas's lab has identified key molecules in the axon's navigation system that govern a basic event common to all nervous systems: making axons grow from one side of the brain to the other. 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, and its importance is underscored by the large number of nerve cells that project their axons across the midline to the opposite side.

Using a set of axon-targeted reporter molecules, Thomas has identified a number of axon guidance molecules, including a receptor called Derailed and its ligand, Wnt5, which together control how axons cross the midline of the nervous system.

Axons, it turns out, do not cross the midline randomly. Instead, they choose specific routes, or tracts. In Drosophila, crossing axons choose one of two tracts. The Derailed receptor is expressed on the growth cones of all nerve cells that cross in one of the tracts. Wnt5 is secreted by nerve cells that cross in the other tract, and by binding to Derailed, it acts as a repellent to keep the Derailed-expressing axons from wandering off the beaten tract.

Both Derailed and Wnt5 belong to larger families of related molecules, and Thomas has found that their relatives control additional axon guidance events. Recent studies have revealed that in mammals, the molecule that corresponds to Derailed is also a receptor for Wnt proteins and that it too is involved in guiding axons. What that means is 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.

Lab Photo

Left to right:
Seated first: Jill Nanadiego, Renee Read, John Thomas Standing second: Noel Moya, Shingo Yoshikawa, Jason Goode, Martin Fugere, Biao Wang

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John B. Thomas

Faculty

John B. Thomas

John B. Thomas

Professor
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.

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