Evidence for axonal protein synthesis was first published more than two decades ago. The vertebrate axonal translational machinery is organized as periaxoplasmic ribosomal plaques (PARPs), first described in 1996. The demonstration that the axonal territory has its own protein synthesis machinery was initially controversial, but now is generally accepted. Axonal protein synthesis expands the scope of our understanding of both normal and pathological physiology of central and peripheral axons. Our analyses of axonal functions such as growth, guidance, regeneration, and plasticity must now incorporate the possibility of dependence on a local gene expression system. While axonal protein synthesis solves problems with protein turnover, it creates new questions about stability and origins of the proteins and messenger RNAs found in periaxoplasmic ribosomal plaques. In this FIRCA application, we hypothesize that the axonal ribosomes, the myosin- Va associated with them, and/or the messenger RNAs associated with them are supplied to the axon by Schwann cells. To test the first two aspects of this hypothesis, we will determine the origin (neuronal or glial) of myosin-Va and the transcript encoding it using transgenic mice in which a tagged myosin-Va is expressed specifically in glial cells. Second, to determine the origin of axonal ribosomes, we will use transgenic mice in which a tagged ribosomal protein is expressed specifically in glial cells or neurons. This research will be done primarily in Uruguay at the Instituto de Investigaciones Biolsgicas Clemente Estable in collaboration with Dr. Josi Roberto Sotelo as an extension of NIH grant R01GM066901.
An understanding of the communication between the axons of neurons and the Schwann cells that ensheath and myelinate them is essential in the development of therapies to regenerate nervous system function after injury and disease. If the underlying hypothesis of this application is correct, it may be possible to directly supplement or program axons with messenger RNAs and proteins, bypassing the neuronal cell body, which can be up to three feet away.
|Sotelo, Jose Roberto; Canclini, Lucia; Kun, Alejandra et al. (2014) Glia to axon RNA transfer. Dev Neurobiol 74:292-302|
|Sotelo, Jose R; Canclini, Lucia; Kun, Alejandra et al. (2013) Myosin-Va-dependent cell-to-cell transfer of RNA from Schwann cells to axons. PLoS One 8:e61905|
|Sotelo-Silveira, Jose Roberto; Calliari, Aldo; Kun, Alejandra et al. (2011) Localization of mRNA in vertebrate axonal compartments by in situ hybridization. Methods Mol Biol 714:125-38|
|Wöllert, Torsten; Patel, Anamika; Lee, Ying-Lung et al. (2011) Myosin5a tail associates directly with Rab3A-containing compartments in neurons. J Biol Chem 286:14352-61|
|Salerno, Veronica P; Calliari, Aldo; Provance Jr, D William et al. (2008) Myosin-Va mediates RNA distribution in primary fibroblasts from multiple organs. Cell Motil Cytoskeleton 65:422-33|