Molecular Mechanisms of Trigeminal Development

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Ongoing collaborations between neuroscientists at the Washington University School of Medicine, Medical College,of Ohio, and Louisiana State University will reveal molecular mechanisms that control the development of mammalian sensory systems. The trigeminal (V) system, inclusive of the whisker-to-barrel pathway, will be used as a model to test hypotheses pertaining to: 1) chemotropic and synaptotrophic actions of neurotrophins in the differentiation of primary afferent neurons; 2) neurotrophic actions upon pattern formation in primary afferents; 3) actions of suspected axon guidance molecules (neurotrophins, Slits, others) in V axon development; 4) transcriptional mechanisms of primary afferent and second-order neuron development; 5) mechanisms by which serotonin and ephrins control thalamocortical axon growth. This renewal application focuses on mechanisms of axon and cell development in the rodent somatosensory periphery and in the brain pathways that conduct somatosensory information. It builds on unparalleled expertise in studies of the V system and adds powerful new approaches from molecular biology. There are 4 Projects and 2 Cores: Project 1 will evaluate the role of the neurotrophins NGF, NTS and GDNF family ligands in peripheral and central branching and functional connectivity of V ganglion cells; it exploits knockouts of NGF, NTS or GDNF and a proapoptotic gene (bax) to test the hypothesis that these molecules have specific tropic effects on the branching patterns of V ganglion cells. Project 2 will evaluate the role of axon guidance molecules (Slits, and their Robo receptors) in the formation of connections between the whiskerpad, V ganglion, V brainstem nuclei and somatosensory thalamus. Project 3 builds on the important new finding that certain transcription factors are necessary for specifying the central targets of the V ganglion (the V brainstem complex), and that this specification is reflected in thalamic and cortical development. It is hypothesized that Lmxlb controls a cascade of downstream genes, in addition to Drg11. Project 4 tests the hypothesis that ephrin/Eph interactions form boundaries within and around the cortical whisker-barrel field that determine the morphology of developing thalamocortical axons both in normal development and when such morphologies are perturbed by elevated serotonin levels in the cortex. Core A will provide molecular biology oversight/expertise, electron microscopy, stereology, pattern analyses, statistical oversight/expertise, administrative support, peer review, and ensure timely communication between projects. Core B will selectively label V axons in embryonic mice and provide standardized and unbiased tissue processing, microscopic evaluations and documentation of these axonal projections.