Specification of neuronal identity and connectivity
Research in the lab focuses on defining the developmental programs that direct the assembly of neural circuits. The ability to move is a simple behavior displayed by all organisms, and many of the circuits essential for locomotor behaviors reside within the spinal cord. The relatively well defined anatomical and physiological features of spinal neurons provide an attractive system to explore the early steps in neural circuit assembly. We use genetic manipulations in chick and mouse to define how neural identity influences the specificity of connections between neurons with their targets.
We have found that a large group of transcription factors belonging to Hox gene family are critical for the selective connections made between motor neurons in the spinal cord and their targets in the periphery. The patterned expression of Hox proteins by other classes of neurons, such as sensory neurons and interneurons, suggests Hox proteins may contribute to more generally to the formation of locomotor circuits. By further defining the basic logic of the Hox transcriptional networks involved in neuronal fate specification, and the identity of the target effectors of these nuclear proteins, we hope to be able to understand the individual molecular elements that control neural circuit assembly.
What are the molecular events controlling neuronal identity in the spinal cord?
Hox proteins are expressed broadly throughout the embryo, and within the spinal cord the same Hox factor can be expressed by multiple neuronal classes. These observations raise the question of how Hox proteins control gene expression in individual neuronal subtypes. Studies in Drosophila and other model systems have provided evidence that the specificity of Hox function is determined through interactions with other DNA-binding proteins. We have found that a member of the large family of forkhead homeodomain (Fox) proteins, FoxP1, is selectively expressed by the motor neuron subtypes that are sensitive to the activities of Hox proteins. We are currently investigating how the concerted actions of Hox and Fox proteins contribute to motor neuron connectivity.
What are the downstream effectors of Hox proteins in defining motor axon trajectories?
The mechanisms by which Hox protein expression in motor neurons determines the selection of muscle targets in the limb are not known. Genes controlled by Hox factors may include other transcription factors, or cell surface proteins that mediate specific interactions between motor axons and positional cues in the developing limb bud. One objective of our future research will be to identify Hox targets, in order to understand the genetic pathways that determine the specificity of motor neuron-muscle connectivity.
Do Hox proteins function in other neuronal classes involved locomotor circuit assembly?
One of the simplest circuits in the spinal cord is the monosynaptic stretch-reflex circuit; consisting of a motor neuron, a sensory neuron, and a muscle target. We have found that the expression of Hox proteins in muscle sensory neurons parallels the segment-specific Hox patterns in motor neurons, raising the intriguing possibility that Hox factors are involved in the formation of specific stretch-reflex circuits. A potential role for Hox factors in sensory-motor connectivity will be explored in this system using gene-targeting strategies in mouse to generate motor and sensory neuron-specific Hox mutants. A potential outcome of these studies is that altering expression of Hox factors in sensory and motor neurons will lead to the failure of sensory neurons to innervate their appropriate motor neuron targets. This hypothesis will be tested using anatomical assays to trace the projections of sensory and motor axons, and to define the molecular properties of their monosynaptic connections.