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In Situ Visualization of Axon Growth and Growth Cone Dynamics in Acute Ex Vivo Embryonic Brain Slice Cultures
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The Krüppel-Like Factor Gene Target Dusp14 Regulates Axon Growth and Regeneration
Joana Galvao1,2, Keiichiro Iwao3, Akintomide Apara3
1Byers Eye Institute, Stanford University, Palo Alto, California, United States.
Investigative Ophthalmology & Visual Science
|June 4, 2018
Summary
Scientists identified a new pathway involving KLF9 and Dusp14 that limits axon regeneration in the central nervous system (CNS). Modulating this pathway could promote nerve repair after injury.
Area of Science:
- Neuroscience
- Molecular Biology
- Regenerative Medicine
Background:
- Adult central nervous system (CNS) neurons possess limited intrinsic axon regeneration capacity following injury.
- Krüppel-like transcription factors (KLFs) influence intrinsic axon growth, but downstream molecular mechanisms remain largely unknown.
Purpose of the Study:
- To elucidate the downstream molecular targets of KLFs that regulate axon growth and regeneration in CNS neurons.
- To investigate the role of identified downstream genes in the intrinsic growth capacity and post-injury regeneration of retinal ganglion cells (RGCs).
Main Methods:
- Retinal ganglion cells (RGCs) were transduced to express specific KLFs (KLF9, KLF16, KLF7, KLF11).
- Microarray analysis identified downstream genes, with Dual-specificity phosphatase 14 (Dusp14) selected for further study.
- Dusp14 function was manipulated using genetic and pharmacologic approaches to assess its impact on neurite outgrowth, cell survival, and optic nerve regeneration in vivo.
Main Results:
- Dusp14 was identified as a critical gene target downstream of KLF9, suppressing axon growth and regeneration in RGCs.
- The KLF9-Dusp14 pathway was found to inhibit mitogen-activated protein kinase (MAPK) activation, crucial for neurotrophic signaling, RGC survival, and axon elongation.
- Reducing Dusp14 expression or inhibiting its function enhanced in vitro axon growth and promoted optic nerve regeneration post-injury in vivo.
Conclusions:
- The study links intrinsic and extrinsic regulators of axon growth by identifying the KLF9-Dusp14 pathway.
- Modulating the KLF9-Dusp14 pathway presents a potential therapeutic strategy for enhancing CNS axon regeneration after injury.
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