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microtubule-binding proteins ( Takei et al., 1997 ), intermediate filaments
( Colucci-Guyon et al., 1994; Elder, Friedrich, Bosco, et al., 1998; Elder,
Friedrich, Kang, et al., 1998; Lariviere, Nguyen, Ribeiro-da-Silva, &
Julien, 2002; Zhu, Couillard-Despres, & Julien, 1997 ), or adhesion
receptors (L1, NCAM, or integrins) ( Cohen et al., 1998; Suzuki &
Takeichi, 2008; Werner et al., 2000 ) causes hypoplasia or mistargeting of
selected axon tracts, demonstrating their involvement in developmental
axon growth.
Maturing neurons also undergo fundamental metabolic and transcriptional
changes. For example, neurons in the maturing retina and cortex display
reduced phosphorylation of S6 kinase, indicative of a reduced capacity
for protein translation ( Liu et al., 2010; Park et al., 2008 ). The expression
of many transcription factors also changes as CNS neurons age, with
c-Jun, Stat3, Sox11, and KLFs as notable examples ( Arlotta et al., 2005;
Herdegen & Leah, 1998; Kim et al., 2008; Moore et al., 2009; Wang et al.,
2007 ). In the case of Klf7, genetic deletion results in mistargeting and
hypoplasia of cortical efferent axon tracts ( Laub et al., 2005 ). Moreover, as
discussed in Section 2.3 , forced overexpression of transcriptionally active
KLF7 enhances axon growth ability in mature cortical neurons, highlighting
the importance of this transcription factor for embryonic axon growth
( Blackmore, Wang, et al., 2012 ).
An interesting feature of these genes implicated in developmental axon,
however, is that loss of any single gene generally does not result in wide-
spread failure of axon growth per se but rather mistargeting or partial reduc-
tion in axon number ( Lariviere & Julien, 2004; Laub et al., 2005; Lin et al.,
2011; Poulain & Sobel, 2010; Suzuki & Takeichi, 2008 ). To some extent,
this may reflect the presence of functionally redundant genes. For instance,
dual knockout of microtubule-binding proteins causes more pronounced
disruption of cortical efferent pathways than any single knockout ( Deuel
et al., 2006; Koizumi, Tanaka, & Gleeson, 2006; Takei, Teng, Harada, &
Hirokawa, 2000 ). These findings suggest that axon growth by immature
neurons may be robust in the sense that it persists despite the loss of
individual genes, although specific aspects of axon growth may be more
sensitive (midline-crossing defects of the corpus callosum and anterior
commissures, for instance, are noted in many of the knockout examples
earlier). If so, it may also be unlikely that any single gene can explain
the difference in regenerative capacity between immature and mature
neurons, underscoring the need to widen the search for genes and gene
networks that regulate axon growth ability.
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