Perelman School of Medicine at the University of Pennsylvania

Granato Lab

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Axonal de- and regeneration

Following injury axons of the peripheral nervous system have the remarkable ability to regenerate reconnect with their original targets. Surprisingly, the number of regenerating axons- even using best surgical practices- is estimated to be lower than 30%, thereby significantly reducing functional regneration. Yet despite its clinical relevance the molecular program and the cellular mechanisms that enable regenerating axons to navigate across the lesion site towards their original synaptic targets, are not well understood. Using transgenic expression of fluorescently tagged proteins in combination with genetic mutants, we are now investigating the cellular interaction between injured axons and neighboring glial cells to decipher the molecular-genetic program underlying peripheral nerve regeneration.

Larval zebra- fish as a model for CNS regeneration: In contrast to mammals, zebrafish exhibit a well-documented capacity for spontaneous optic nerve regeneration, providing a unique opportunity to define the dynamic interactions between injured retinal ganglion cell ( RGC) axons and glia, and to decipher the molecular mechanisms underlying axonal guidance during optic nerve regeneration. We have recently established a powerful assay to transect the optic nerve and monitor axonal and functional regeneration in larval zebrafish. We find that RGC axonal regeneration is rapid, with re-innervating axons entering the optic tectum by 48 hours post transection, independent of cell death or RGC proliferation. This provides a rare model to uncover guidance mechanisms critical for spontaneous optic nerve regeneration independently of the confounds of neural survival and neurogenesis.

For rotation projects available in this area click here

Harvey, B.M., Baxter, M. and Granato, M. (2019). Optic nerve regeneration in larval zebrafish exhibits spontaneous capacity for retinotopic but not tectum specific regeneration. PLoS One 14(6):e0218667. PMID: 31220164. pdf

Ducommun-Priest, M. Navarro, M.F., Bremer, J., Granato, M. (2019) Dynein promotes sustained axonal growth and Schwann cell remodeling early during peripheral nerve regeneration. PLoS Genetics, 15(2)e1007982. pdf

Gribble, K. D., Walker, L.J., Saint-Amant, L., Kuwada, J.Y. Granato, M. (2018) The synaptic receptor Lrp4 promotes peripheral nerve regeneration. Nature Communications, 19;9(1):2389pdf

Isaacman-Beck, J., Schneider, V., Franzini-Armstrong, C, Granato, M. 2015: The lh3 glycosyltransferase directs target selective peripheral nerve regeneration. Neuron 88, 1-13. pdf.

Rosenberg, A., Isaacman-Beck, J, Franzini-Armstrong, C, Granato, M. 2014: Schwann cells and DCC direct regenerating motor axons towards their original path. J. Neuroscience (44) 14668-81. pdf This work is featured in 'This week in the Journal'

   Rosenberg, A., Wolman, M, Franzini-Armstrong, C, Granato, M. In vivo macrophage-nerve interactions following peripheral nerve injury. 2012. J. Neuroscience (32), 4440-56. pdf and comment