Regulation of intrinsic axon growth ability at retinal ganglion cell growth cones

Invest Ophthalmol Vis Sci. 2014 Jun 6;55(7):4369-77. doi: 10.1167/iovs.14-13882.

Abstract

Purpose: Mammalian central nervous system neurons fail to regenerate after injury or disease, in part due to a progressive loss in intrinsic axon growth ability after birth. Whether lost axon growth ability is due to limited growth resources or to changes in the axonal growth cone is unknown.

Methods: Static and time-lapse images of purified retinal ganglion cells (RGCs) were analyzed for axon growth rate and growth cone morphology and dynamics without treatment and after manipulating Kruppel-like transcription factor (KLF) expression or applying mechanical tension.

Results: Retinal ganglion cells undergo a developmental switch in growth cone dynamics that mirrors the decline in postnatal axon growth rates, with increased filopodial adhesion and decreased lamellar protrusion area in postnatal axonal growth cones. Moreover, expressing growth-suppressive KLF4 or growth-enhancing KLF6 transcription factors elicits similar changes in postnatal growth cones that correlate with axon growth rates. Postnatal RGC axon growth rate is not limited by an inability to achieve axon growth rates similar to embryonic RGCs; indeed, postnatal axons support elongation rates up to 100-fold faster than postnatal axonal growth rates. Rather, the intrinsic capacity for rapid axon growth is due to both growth cone pausing and retraction, as well as to a slightly decreased ability to achieve rapid instantaneous rates of forward progression. Finally, we observed that RGC axon and dendrite growth are regulated independently in vitro.

Conclusions: Together, these data support the hypothesis that intrinsic axon growth rate is regulated by an axon-specific growth program that differentially regulates growth cone motility.

Keywords: CNS; KLF; axon; filopodia; growth cone; lamellipodia; regeneration.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Animals, Newborn
  • Axons / metabolism
  • Cell Proliferation
  • Disease Models, Animal
  • Female
  • Growth Cones / metabolism*
  • Male
  • Nerve Regeneration
  • Neurons / metabolism
  • Neurons / pathology
  • Optic Nerve / growth & development*
  • Optic Nerve / metabolism
  • Optic Nerve / pathology
  • Rats
  • Rats, Sprague-Dawley
  • Retinal Diseases / metabolism
  • Retinal Diseases / pathology*
  • Retinal Ganglion Cells / metabolism
  • Retinal Ganglion Cells / pathology*
  • Stress, Mechanical