Trigeminal ganglion axons convey orofacial sensation to the brain via synapses in the brainstem trigeminal nuclei. During wiring of this pathway, peripheral and central trigeminal axons exhibit highly specific target- directed growth, target recognition, and elaboration of synaptic terminals. Molecular mechanisms underlying these processes are largely unknown. In recent years, several families of molecules, which guide growing axons, have been identified. These molecular signals are remarkably conserved between species from flies to mammals. Some of these molecules attract, while others repel growing axons, thus directing their pathway choice. Axon guidance involves not only pathway formation but also recognition of targets and elaboration of terminal branches and formation of synaptic terminals within targets. Molecular signals, which direct this latter phase of axon development, are not well understood. Recently Slit2, a member of the Slit family of proteins have been implicated as a potent branching factor for sensory neurons. During development of the trigeminal pathway mRNA for Slits and Robo receptors are expressed differentially. While Robol and Robo2 expression is prominent in the trigeminal ganglion of the three Slits, Slit-2 mRNA appears in the brainstem trigeminal nuclei just as trigeminal ganglion axons begin arborizing in this target. In the main peripheral target of the trigeminal ganglion, the whisker pad, Slit mRNAs are expressed differentially around the whisker follicles. Our main objective is to elucidate the role of Slit2 in switching trigeminal axons from elongation to branching/arborization phase. We propose to experimentally test the role of Slit2 in trigeminal axon branching and arborization using an in vitro model of the rodent trigeminal pathway. Additionally, we will examine the role of other Slit proteins in guiding trigeminal axons in the periphery and trigeminal lemniscal axons in the CMS.
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