It is currently unknown why mature, central nervous system (CNS) neurons fail to regenerate after injury, and how this failure depends on developmental changes in gene expression. Mature RGCs fail to regenerate after their axons are severed, yet axons in the embryonic CNS can regenerate after injury. The loss of this embryonic regenerative ability correlates with the loss of RGCs'intrinsic ability to rapidly extend axons. Here we propose to investigate the regulation of RGC axon growth and regenerative capacity by the Kruppel-Like family of transcription factors. Specifically, we have identified a family of developmentally regulated transcription factors in the Kruppel-Like Factor (KLF) family that regulate axon growth of RGCs in vitro and in vivo. In the first aim we determine how KLF family members differ in their recruitment of co-activators and co-repressors, and how such co- factors regulate RGC axon growth with the KLFs. In the second aim we will characterize the gene targets of KLF family members in RGCs in vitro and in vivo. In the third aim we will ask whether manipulating expression of multiple KLFs in vitro and in vivo alters RGC axon growth during development or after optic nerve injury. Our goal is to revert mature, postnatal RGCs to their embryonic axon growth ability, and to enhance RGC regeneration after optic nerve injury in vivo. Our ultimate goal is to develop new treatments to promote RGC regeneration after injury in ocular diseases including glaucoma, retinal ischemia, optic neuritis and optic neuropathies, and to extend our understanding to more broadly promote CNS regeneration, for example after spinal cord injury or in neurodegenerative disease.

Public Health Relevance

Retinal ganglion cells (RGCs) lose their ability to regenerate, but it is not known why. Developmentally regulated transcription factors in the Kruppel-Like Factor family may control RGCs'intrinsic capacity for rapid axon growth and regeneration, but the cellular and molecular details of this process remain to be discovered. Our hope in investigating this process is to understand why RGCs fail to regenerate after injury or in degenerative diseases such as glaucoma and ischemic optic neuropathy.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Anterior Eye Disease Study Section (AED)
Program Officer
Agarwal, Neeraj
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
Zip Code
Wang, Jianbo; Galvao, Joana; Beach, Krista M et al. (2016) Novel Roles and Mechanism for Krüppel-like Factor 16 (KLF16) Regulation of Neurite Outgrowth and Ephrin Receptor A5 (EphA5) Expression in Retinal Ganglion Cells. J Biol Chem 291:18084-95
Fang, Jiahua; Shaw, Peter X; Wang, Yan et al. (2016) Krüppel-Like Factor 4 (KLF4) Is Not Required for Retinal Cell Differentiation. eNeuro 3:
Trakhtenberg, Ephraim F; Morkin, Melina I; Patel, Karan H et al. (2015) The N-terminal Set-? Protein Isoform Induces Neuronal Death. J Biol Chem 290:13417-26
Trakhtenberg, Ephraim F; Wang, Yan; Morkin, Melina I et al. (2014) Regulating Set-?'s Subcellular Localization Toggles Its Function between Inhibiting and Promoting Axon Growth and Regeneration. J Neurosci 34:7361-74
Steketee, Michael B; Oboudiyat, Carly; Daneman, Richard et al. (2014) Regulation of intrinsic axon growth ability at retinal ganglion cell growth cones. Invest Ophthalmol Vis Sci 55:4369-77
Trakhtenberg, Ephraim F; Goldberg, Jeffrey L (2012) Epigenetic regulation of axon and dendrite growth. Front Mol Neurosci 5:24
Blackmore, Murray G; Wang, Zimei; Lerch, Jessica K et al. (2012) Kruppel-like Factor 7 engineered for transcriptional activation promotes axon regeneration in the adult corticospinal tract. Proc Natl Acad Sci U S A 109:7517-22
Chang, Elma E; Goldberg, Jeffrey L (2012) Glaucoma 2.0: neuroprotection, neuroregeneration, neuroenhancement. Ophthalmology 119:979-86
Santos, Andrea Rachelle C; Corredor, Raul G; Obeso, Betty Albo et al. (2012) ?1 integrin-focal adhesion kinase (FAK) signaling modulates retinal ganglion cell (RGC) survival. PLoS One 7:e48332
Johnstone, Andrea L; Reierson, Gillian W; Smith, Robin P et al. (2012) A chemical genetic approach identifies piperazine antipsychotics as promoters of CNS neurite growth on inhibitory substrates. Mol Cell Neurosci 50:125-35

Showing the most recent 10 out of 20 publications