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The Assembly and Function of Sensory-Motor Circuitry
Summary: Thomas Jessell's research explores the mechanisms that direct the assembly of neural circuits and how the organization of these circuits controls vertebrate behavior. He is examining these general problems through an analysis of circuits in the spinal cord that coordinate locomotor behavior.
Linking Motor Neuron Identity and Muscle Target Connectivity
The task of establishing appropriate patterns of connectivity is at its most challenging in the vertebrate central nervous system, where hundreds of different neuronal types are required to form thousands of synaptic connections, each with a selective subset of potential targets. Some insights into the mechanisms that link neuronal identity and connectivity have come from the study of one of its major neuronal classes—the spinal motor neuron. From the perspective of locomotor control, one critical aspect of motor neuron differentiation is the formation of precise connections between motor neurons and target muscles in the developing limb. We have been examining how motor neurons acquire specialized identities that permit them to form specific target connections.
The molecular logic that links motor neuron identity and target muscle connectivity has long remained elusive, but our recent work has shown that the selectivity of expression of transcription factors determines many aspects of neuronal specificity in this circuit. We have found that motor neuron subtype identity is determined by the selective activities of Hox class homeodomain proteins. Three classical features of motor neurons that project to specific target muscles in the limb—their remarkable 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. Thus, changing the Hox profile of motor neurons elicits a predictable change in target muscle connectivity.
More recent studies have provided evidence that Hox genes determine the specificity of target muscle connections by regulating downstream transcription factors that exhibit more restricted profiles of expression. Some of these downstream factors, LIM and Nkx class homeodomain proteins, help to establish motor axon trajectories to specific muscle targets. And some of the surface receptors that mediate their activities have been defined. For example, LIM homedomain proteins control the expression of Eph receptor kinases on motor axons. Other classes of transcription factors, notably the ETS proteins, control the expression of cell surface recognition molecules, notably type II cadherins, which in turn direct the clustering of motor neurons into pools. Thus, emerging evidence indicates that 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.
More generally these studies reveal that the challenge of specifying 100 or so distinct subclasses of motor neurons, each projecting to a specific target cell group, can be met by deploying the regulatory interactions of members of a structurally related and chromosomally clustered set of Hox transcription factors. The informational content resident in the combinatorial use of Hox proteins far exceeds the requirements for motor neuron diversification, raising the possibility that Hox proteins have additional roles in the assembly of spinal circuits. Indeed, complex patterns of Hox protein expression also define spinal interneurons and sensory neurons, consistent with the idea that Hox proteins contribute more extensively to the formation of locomotor circuits. More generally, the self-organizing features inherent in this Hox transcriptional regulatory network could help to endow developing spinal motor circuits with their apparent high degree of genetic determination.
Establishing Sensory Feedback Connections with Motor Neurons
The coordination of motor output depends critically on sensory feedback information provided by proprioceptive sensory neurons. This sensory-motor reflex circuit involves two main classes of sensory neurons. Group Ia proprioceptive afferents relay sensory information from muscle spindles and form direct connections with the dendrites of motor neurons. Group Ib afferents convey information from Golgi tendon organs and form only indirect connections with motor neurons. At a finer level of specificity, group Ia afferents form preferential connections with motor neurons that innervate the same muscle group.
The selectivity of proprioceptive afferent–motor neuron connectivity is thought to have 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 appears to be a primary determinant of the projection pattern of sensory axons within the spinal cord. In turn, the expression and activity of Runx3 in sensory neurons is gated by neurotrophin signals derived from the periphery, and by expression of the ETS transcription factor Er81. Elimination of Er81 function prevents the formation of direct connections between proprioceptive sensory afferents and motor neurons, abolishing coordinated motor output. These studies reveal that common sets of transcription factors control sensory and motor projection patterns in the developing spinal cord.
In turn, these sensory neuron transcription factors regulate sensory-motor connectivity, in part through expression of cell surface recognition proteins of the plexin and cadherin families. Plexins serve as receptors for semaphorin ligands, and our recent studies indicate that the initial trajectory of proprioceptive axons within the spinal cord is defined by Sema6-PlexinA1 signaling. We are examining whether and how the selectivity of semaphorin and type II cadherin expression by sensory and motor neurons influences the formation and specificity of monosynaptic sensory-motor connections.
Dissecting Interneuron Circuits That Coordinate Locomotion
Local interneuron circuits have a major role in the coordination of motor behaviors. The simple repetitive movements that underlie locomotion are generated by localized neural networks known as central pattern generators (CPGs). These circuits provide a model system for studying how neuronal networks generate simple behaviors. The local interneuron circuits that contribute to the vertebrate locomotor CPG reside in the spinal cord and generate the elemental patterns of motor activity that underlie swimming and walking movements. Little is known, however, about the organization of the locomotor CPG circuit in walking mammals, in part because of the difficulty in identifying and manipulating its intrinsic interneuronal components.
One potential strategy for selective manipulation of defined sets of CPG interneurons has emerged from our studies on interneuron subtypes and their progenitors in the developing spinal cord. Like motor neurons, spinal interneurons can be distinguished by the restricted expression of homeodomain transcription factors. We have found that graded sonic hedgehog signaling specifies four cardinal sets of ventral interneurons—V0, V1, V2, and V3 neurons—each with a different intraspinal projection pattern and target connectivity. Genetic and physiological studies performed with the lab of Martyn Goulding (Salk Institute for Biological Studies) have shown that V0 interneurons have a key role in establishing left-right alternation in motor activity, and thus are critical elements of the interneuronal circuitry that directs locomotor behavior.
Yet the classical physiological descriptions of spinal interneurons indicate a greater diversity than is revealed by these four cardinal interneuron subsets. In recent studies, we have found that these major interneuron classes can be further subdivided, on the basis of transcription factor expression, into more discrete neuronal classes. The selectivity of transcription factor expression by subsets of interneurons thus provides a powerful and systematic way of assessing local interneuronal function, through the neuronal subtype-restricted expression of toxins that kill neurons or ion channel proteins that regulate their activity. In this way, it should be possible to dissect the core logic of the interneuronal circuits that gate sensory-motor transmission and generate the rhythm and pattern of motor output. More generally, our findings point to the utility of transcription factors as genetic entry points for the functional analysis of brain circuits and mammalian behavior.
These studies have been supported by grants from the National Institute of Neurological Disorders and Stroke, the National Institute of Mental Health, the Leila and Harold Mathers Foundation, Project A.L.S., the Wellcome Trust, the Human Frontier Science Program, the Sackler Foundation, and the George Frederick Jewett Foundation.
Last updated: November 4, 2008
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