Thomas Jessell, Ph.D.Claire Tow Professor, Neuroscience and Biochemistry & Molecular Biophysics
Co-director of the Mind Brain Behavior Initiative, Co-director of The Kavli Institute for Brain Science
Investigator Howard Hughes Medical Institute
Area of Research
Stem Cell Biology, Axon Pathfinding and Synaptogenesis, Synapses and Circuits, Neurogenetics, Motor Systems
Molecular mechanisms of neuronal differentiation, axon guidance, and cell recognition in the developing vertebrate nervous system
The Assembly and Organization of Sensory-Motor Circuits
The task of assembling functional neural circuits is at its most challenging in the central nervous system, where hundreds of different neuronal types form thousands of synaptic connections, each with a selective subset of potential targets. We have been examining the developmental organization and function of neural connections through a focus on the spinal circuits involved in the control of movement.
Motor Neuron Diversity and Connectivity: We are exploring the mechanisms that link neuronal identity and connectivity through an analysis of spinal motor neurons. Our recent work has shown that three classical features of organization of motor neurons that project to specific target muscles in the limb—their diversity, their stereotyped position, and their connectivity—are established by a Hox transcriptional regulatory network. These Hox interactions both constrain motor pools to specific rostrocaudal levels of the spinal cord and drive the diversification of motor neurons at a single segmental level. Moreover, this Hox regulatory network directs selective motor neuron connectivity with limb muscles. The output of this motor neuron Hox regulatory circuit is mediated through the expression of downstream transcription factors and surface molecules, which in turn direct target muscle connectivity and motor neuron sorting.
Sensory Feedback Connections with Motor Neurons: The coordination of motor output depends critically on sensory feedback information provided by proprioceptive sensory neurons. The selectivity of proprioceptive afferent–motor neuron connectivity has its basis in the formation of distinct afferent termination zones in the spinal cord, as well as in the recognition of specific motor neuron targets. We have found that the specificity of proprioceptive axonal inputs to motor neurons is controlled by two main classes of transcription factors, Runx and ETS proteins. The level of Runx3 expression by sensory neurons is a primary determinant of the projection pattern of sensory axons within the spinal cord. These sensory transcription factors regulate sensory-motor connectivity, in part through expression of cell surface recognition proteins of the plexin and cadherin families. We are now examining how the selectivity of expression of these recognition proteins by sensory and motor neurons influences the formation and specificity of sensory-motor connections.
Dissecting Interneuron Circuits That Control Motor Behavior: Interneurons have a major role in the coordination of motor behavior, but little is known about their organization, in part because of the difficulty in identifying and manipulating specific interneuron populations. We have identified transcription factors that define specific sets of spinal interneurons, each with a different intraspinal projection pattern and target connectivity. The selectivity of transcription factor expression permits a systematic assessment of the contribution of these neurons to specific motor behaviors, through the expression of toxin or channels that regulate the neural activity. These studies are starting to reveal the core logic of local circuits that gate sensory-motor transmission and pattern motor output.
Dasen, J., De Camilli, A., Wang, B., Tucker, P.W. and Jessell, T.M. (2008). Hox repertories for motor neuron diversity and connectivity gated by a single accessory factor, FoxP1. Cell, 134, 304-316.
Chen, A.I., de Nooij, J.C. and Jessell, T.M. (2006). Graded activity of transcription factor Runx3 specifies the laminar termination pattern of sensory axons in the developing spinal cord. Neuron 49, 395-408.
Dasen, J.S., Tice, B.C., Brenner-Morton, S. and Jessell, T.M. (2005). A Hox regulatory network establishing motor neuron pool identity and target muscle connectivity. Cell 123, 477-491.
Price, S.R., De Marco Garcia, N.V. Ranscht, B. and Jessell, T.M. (2002). Regulation of motor neuron pool sorting by differential expression of type II cadherins. Cell, 109, 205-216.
Arber, S., Ladle, D., Lin, J., Frank, E. and Jessell, T.M. (2000). ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons. Cell, 101, 485-498.
Jessell, T.M. (2000) Neuronal specification in the spinal cord: inductive signals and transcriptional codes. Nature Reviews Genetics. 1, 20-29.