Biology Reference
In-Depth Information
1. INTRODUCTION
Neurons of the mammalian central nervous system (CNS) generally
do not regenerate axons after injury, whereas those of the peripheral nervous
system (PNS) do. What accounts for such a disparity in the regenerative abil-
ity between these two systems? This question has been a subject of intense
investigation in neuroscientific research. The past decade has seen much
progress toward understanding why injured CNS axons fail to regenerate.
One contributing factor is the growth-inhibitory environment of the
CNS, with several constituents of the CNS myelin and glial scar at the lesion
site identified as barriers of axon regeneration (
Filbin, 2003; Fitch & Silver,
2008; Yiu &He, 2006
). Accordingly, pharmacological and genetic strategies
that neutralize these extrinsic inhibitors yielded some degree of axon
regeneration. However, while some injured axons are able to regrow
into the permissive grafts, the majority of adult neurons fail to regenerate
axons even when provided with permissive substrates (
Aguayo, David, &
Bray, 1981; Aguayo et al., 1990; Richardson, McGuinness, & Aguayo,
1980
). Thus, the prevailing view is that, in addition to the environmental
impediments, axon regeneration failure is due also to a limited growth
capacity of adult CNS neurons. What neuron-intrinsic factors could limit
axon regeneration in the mammalian CNS? Advances in our ability to
modulate gene expression in cell-specific and time-specific manners using
genetically modified animals, as well as the emergence of high-
throughput screening techniques have transformed our ways of
investigating this question. Researches utilizing these and other analytical
models have elucidated several genetic and molecular signatures within
neurons that influence intrinsic regenerative capacity. They indicate that
the sequential steps of axon regeneration from growth cone generation
and axon extension require modulation of gene transcription and protein
translation at the cell body and axonal level. Recently, considerable
attention has been paid to two intracellular signaling components that
mediate these processes to influence intrinsic axon regrowth capacity in
both the PNS and CNS: PTEN (phosphatase and tensin homologue) and
SOCS3 (suppressor of cytokine signaling 3). In this review, we describe
and summarize the participation of the PTEN and SOCS3 pathways in
the regulation of the process of axon growth and regeneration. We also
discuss the potential molecular and cellular mechanisms by which these
signaling pathways regulate such processes.
