Biology Reference
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an exceptional trait that arose late in evolution, emerges late in the
development of the nervous system, and is restricted to the CNS. This
perspective is hardly new, as the study of successful axon regeneration
and the debate regarding its mechanisms stretch back well over 200 years
(
Ochs, 1977
). In recent decades, a major effort has been to identify
differences in gene expression that might explain differing regenerative
capacity between neurons. Indeed, as discussed below, hundreds of
correlative studies, some including functional tests, have created a large
and perhaps disparate body of knowledge relating gene expression to
regenerative capacity in various neuronal cell types. This review examines
insights into the cell-autonomous control of axon growth that arise from
three commonly used models of successful axon regeneration: the
developing mammalian CNS, the PNS, and nonmammalian nervous
systems. For each, I examine both correlative and functional studies that
link gene expression to regenerative state, with an emphasis on
in vivo
tests of gene function. I then examine the accelerating production of
genome-wide datasets of gene expression in regenerating neurons, and
the emergence of high-throughput screening (HTS) studies to
functionally test differentially expressed genes. Finally, I critically assess
the prospects of comparing these divergent datasets to identify relevant
genes and highlight future directions in gene profiling and HTS in the
study of axon regeneration.
2. COMPARISONS ACROSS CNS DEVELOPMENT
2.1. Correlative and functional tests of gene function
Functional axon regeneration in the immature mammalian CNS has been
demonstrated in the brachium of the superior colliculus, the nigral-striatal
tract, multiple brainstem-spinal projections, and the CST (
Bregman &
Goldberger, 1983; Bregman et al., 1989; Hasan, Keirstead, Muir, &
Steeves, 1993; Kawano, Li, Sango, Kawamura, & Raisman, 2005;
Saunders et al., 1998; Shimizu, Oppenheim, O'Brien, & Shneiderman,
1990; So et al., 1981
). Importantly, prelabeling of injured axons has
confirmed that this axon growth reflects true regeneration, as opposed to
the arrival of late-developing axons (
Bregman & Bernstein-Goral, 1991;
Fry, Stolp, Lane, Dziegielewska, & Saunders, 2003; Hasan et al., 1993
).
The permissive period for regeneration ends at different times in different
tracts, generally occurring within days of the arrival of axons in their
target fields. Notably, experiments that pair age-mismatched explants of
