| Why do central nervous system (CNS) neurons fail to regenerate after injury? For example, retinal ganglion cells (RGCs, a type of CNS neuron) fail to regenerate their axons after optic nerve injury. Overcoming the glial-associated inhibitory environment is not sufficient on its own, suggesting that intrinsic changes within the neurons themselves also contribute. Indeed RGCs lose their intrinsic capacity for rapid axon growth during development. To determine the molecular mechanism for this loss, over 100 developmentally regulated genes were screened in primary neurons for effects on neurite growth. Overexpression of the transcription factor Kruppel-like factor 4 (KLF4) resulted in an approximately 50% decrease in neurite growth. KLF4 overexpression in RGCs results in decreased acquisition of neuronal polarity, neurite growth and neurite initiation in vitro. Furthermore, RGCs lacking KLF4 grow their axons faster in vitro, and demonstrate increased axon regenerative capacity after optic nerve injury in vivo. Further analysis of the KLF family revealed that 15 members are expressed in RGCs, and their overexpression results in differential effects on neurite growth in multiple primary neurons. Many are developmentally regulated in a manner that correlates with their ability to affect neurite growth, such that growth enhancers display decreased expression postnatally, while growth suppressors have increased expression postnatally. RGCs express many neurite growth-suppressing KLFs, and when these are paired with KLF neurite growth enhancers, the suppressive neurite growth phenotype dominates. These data suggest that to further enhance regeneration after injury, we may need to block the function of many growth suppressing KLF family members. Taken together, these results suggest that KLFs play an important role in the intrinsic regulation of axon growth and regeneration and that by manipulating their expression, we may further increase the intrinsic capacity of neurons to grow and regenerate. |
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