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5. CONCLUSIONS AND FUTURE DIRECTIONS
The comparative strategy to identifying the molecular control of axon
growth is now decades old. The basic questions remain: what molecular
mechanisms explain the differences in regenerative potential across age, cell
type, and species, and how can these mechanisms be manipulated to enhance
axon growth and neural repair? When the strategy was launched in the
1980s, it might have been hoped that adult CNS neurons remained funda-
mentally primed for axon growth, and that their elongation was prevented
by the absence of just a few key genes. Work over the ensuing decades, and
particularly the emergence of gene profiling and high-content screening
(HCS) datasets, has made this scenario highly unlikely. Rather, as empha-
sized throughout, axon growth is clearly a complex process that involves
regulated expression of many genes that span diverse functional classes. This
is evident from the sheer number of genes that correlate with regenerative
state, which range from many hundreds to thousands ( Table 3.1 ). It is also
evident from the available functional data. This review has highlighted more
than 30 genes that have been functionally linked to developmental or regen-
erative axon growth in vivo . Notably, knockout and functional blockade of
individual genes generally leads to only partial loss of regenerative growth,
and conversely, individual and dual gene manipulations in CNS neurons
have only partially restored regenerative potential. The HCS datasets tell
a similar story. Thousands of genes have now been functionally tested in var-
ious assays of neurite outgrowth. “Hit” genes are numerous but generally
have moderate effects (i.e., < 50% increase or decrease from baseline). Axon
growth thus appears to be highly robust in the sense that its success involves
large numbers of genes, and mechanisms exist to completely or mostly com-
pensate for loss or gain of function in the great majority.
A second general conclusion to emerge from comparative regenerative
studies is that the relatively low regenerative capacity in adult CNS neurons
reflects both a lower expression of growth-promoting genes and a higher
expression of growth-restrictive genes. One striking example of this comes
from the family of KLF transcription factors. Developing neurons simulta-
neously upregulate growth-suppressive KLF family members and down-
regulate the growth promoters, and in the adult, CNS regeneration is
promoted both by knockdown of growth-suppressive KLF4 and by
increased activity by growth-promoting KLF7 ( Blackmore, Wang, et al.,
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