Biology Reference
In-Depth Information
1. INTRODUCTION
Most neurons in the central nervous system (CNS) of adult mammals
fail to regenerate their axons after injury, constrained both by an inhibitory
environment and by neuron-intrinsic limits to growth (
Afshari,
Kappagantula, & Fawcett, 2009; Benowitz & Yin, 2007; Huebner &
Strittmatter, 2009; Muramatsu, Ueno, & Yamashita, 2009
). Studies in the
early 1980s showed that some CNS axons regenerate into transplants of
peripheral nerves (
David & Aguayo, 1981; Richardson, McGuinness, &
Aguayo, 1980
), raising the hope that widespread regeneration might be
achieved if the environment could be rendered favorable. The ensuing
decades saw tremendous progress in identifying inhibitory signals in the
CNS environment, but regenerative growth from most neuronal
populations has remained modest even when inhibitory factors are
neutralized. Genetic knockout of multiple growth inhibitors, for instance,
fails to improve axonal regeneration in the injured spinal cord,
emphasizing the point that relieving inhibition may be insufficient to
promote robust axon regeneration unless combined with some means to
improve neuron-intrinsic growth capacity (
Lee et al., 2010
). Conversely,
recent gains have been made by manipulating gene expression within
injured CNS neurons. For instance, the Kr¨ppel-like family of
transcription factors (KLFs) was found to regulate intrinsic regenerative
capacity in CNS neurons, and KLF-based manipulations have improved
axon regeneration in the optic nerve and in the corticospinal tract (CST)
(
Blackmore, Wang, et al., 2012; Moore et al., 2009
). Furthermore,
deletion of PTEN and the resulting enhancement of mTOR signaling
produced a remarkable regenerative response in both retinal ganglion cell
(RGC) and CST neurons (
Liu et al., 2010; Park et al., 2008
). The
success of these and other neuron-based strategies has refocused attention
on genes and pathways that act within neurons to regulate their intrinsic
propensity for axon growth.
Axon regeneration succeeds in invertebrate species, in the peripheral
nervous system (PNS) of vertebrates, and in many CNS populations of
cold-blooded vertebrates including fish and amphibians (see
Sections 3.1
and 4.1
). Even in the mammalian CNS, axon regeneration succeeds early
in life and fails only after a developmental transition (
Bregman, Kunkel-
Bagden, McAtee, & O'Neill, 1989; Saunders et al., 1998; So, Schneider, &
Ayres, 1981)
. Thus, the inability to regenerate axons is best viewed as
