![Figure 4 Dusp14 regulates axon regeneration through dephosphorylation of the MAPK family in vivo. (A) No change in Dusp14 expression was detectable at 5 and 14 days after optic nerve crush. (B) Dusp14 expression decreased after intravitreal injection of AAV2-Dusp14-shRNA in vivo (arrows). (C–F) Dusp14 knockdown significantly increased the number of pERK1/2-positive cells (D) and pERK1/2 fluorescent intensity (E) in retinas treated with BDNF. (*P < 0.05, Student's t-test; n = 4 [D, E]) Scale bars: 25 μm in (A) to (C), 500 μm in (D). Error bars, SEM.](https://i0.wp.com/idsc.miami.edu/wp-content/uploads/2020/12/axon-regeneration-940x530-1.jpg?resize=940%2C530&ssl=1)
The Krüppel-Like Factor Gene Target Dusp14 Regulates Axon Growth…
Adult central nervous system (CNS) neurons are unable to regenerate their axons after injury. Krüppel-like transcription factor (KLF) family members regulate intrinsic axon growth ability in vitro and in vivo, but mechanisms downstream of these transcription factors are not known.
Methods
Purified retinal ganglion cells (RGCs) were transduced to express exogenous KLF9, KLF16, KLF7, or KLF11; microarray analysis was used to identify downstream genes, which were screened for effects on axon growth. Dual-specificity phosphatase 14 (Dusp14) was further studied using genetic (siRNA, shRNA) and pharmacologic (PTP inhibitor IV) manipulation to assess effects on neurite length in vitro and survival and regeneration in vivo after optic nerve crush in rats and mice.
Results
By screening genes regulated by KLFs in RGCs, we identified Dusp14 as a critical gene target limiting axon growth and regeneration downstream of KLF9’s ability to suppress axon growth in RGCs. The KLF9-Dusp14 pathway inhibited activation of mitogen-activated protein kinases normally critical to neurotrophic signaling of RGC survival and axon elongation. Decreasing Dusp14 expression or disrupting its function in RGCs increased axon growth in vitro and promoted survival and optic nerve regeneration after optic nerve injury in vivo.
Conclusion
These results link intrinsic and extrinsic regulators of axon growth and suggest modulation of the KLF9-Dusp14 pathway as a potential approach to improve regeneration in the adult CNS after injury.
The Krüppel-Like Factor Gene Target Dusp14 Regulates Axon Growth and Regeneration by Galvao J, Iwao K, Apara A, et al. Invest Ophthalmol Vis Sci. 2018;59(7):2736-2747.