Publication Date




Embargo Period


Degree Type


Degree Name

Doctor of Philosophy (PHD)


Neuroscience (Medicine)

Date of Defense


First Committee Member

Robert W. Keane

Second Committee Member

Sanjoy Bhattacharya

Third Committee Member

Kevin Park

Fourth Committee Member

Jeffrey L. Goldberg


Neurons in the adult mammalian CNS are unable to regenerate their axons after injury. While much is known about the extrinsic inhibitory environment that plays a role, intrinsic changes within neurons themselves also mediate this phenomenon. Previously, Our laboratory found that retinal ganglion cells (RGCs) decrease intrinsic axon growth around birth and members of Krüppel-like transcription factor (KLFs) family mediate this reduction. Overexpression of KLF4 in cultured RGCs and other neurons leads to a decrease in axon growth, and embryonic deletion of KLF4 increases axon growth in vitro and promotes regeneration following optic nerve crush in vivo. Other members of the KLF family are also developmentally regulated and suppress axon growth. For example, KLF9 is up-regulated more than 250-fold during development (more than any other KLF family member) and is a suppressor of neurite growth. It belongs to a subfamily of KLFs known as the Basic Transcription Element-Binding protein (BTEBs), which includes KLFs 13, 14, and 16. All four members of this subfamily share a similar N-terminal structure and suppress neurite growth. As there was a close relationship between the structure of these KLFs and their function in RGCs, I hypothesized that binding partners may play a role in the regulation of these KLFs’ function with respect to axon growth. Using mass spectrometry, I discovered one potential binding partner of the growth-suppressive KLF9 to be the kinase MAPK10/JNK3. This finding raised the hypothesis that KLF9 might be phosphorylated by JNK3 or other kinases, and that phosphorylation may regulate KLF9’s function in axon growth. Deletion of the putative JNK3-binding site in KLF9 blocked the ability of KLF9 to bind JNK3 and to suppress axon growth. Furthermore, I identified two putative phosphorylation sites on KLF9 that when mutated to mimic the phosphorylated state leads to greater axon growth suppression, but when mutated to avoid phosphorylation, prevents KLF9 from suppressing axon growth. Thus JNK3 binding to and phosphorylating KLF9 promotes KLF9-mediated suppression of axon growth. Future experiments will examine whether targeting these phosphorylated and JNK3-binding sites will improve RGC axon regeneration following optic nerve injury in vivo. These experiments have identified new approaches to enhancing axon regeneration in the CNS.


Neurons; Axon Regeneration; Retinal Ganglion Cell; Optic Nerve; KLFs; JNK3