Biology Reference
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2007; Raivich & Makwana, 2007; Stenberg, Kanje, Martensson, & Dahlin,
2011
). The microenvironment also contains molecules that are produced by
the Schwann cells, by invading inflammatory cells as well as by other injured
axons. These substances, like ciliary neurotrophic factor (CNTF) and leu-
kemia inhibitory factor (LIF), can activate the signal transducer and activator
of transcription 3 (STAT3) (
Wang et al., 2009
). Other examples of locally
activated molecules are ERK and c-Jun N-terminal kinase (JNK), which are
activated by phosphorylation. These complexes are shuttled by retrograde
transport with added nuclear localization sequences that allow the translo-
cation to the nucleus. Thereby, these signals are positive injury signals that
are generated at or around the tip of the axon with the purpose of translo-
cation to the nucleus for activation of gene transcription (
Hanz & Fainzilber,
2004, 2006; Lindwall & Kanje, 2005b
)(
Fig. 7.1
).
The transcription of multiple genes is modulated by retrograde signals,
such as the immediate early genes c-Jun and the transcription factors, like acti-
vating transcription factor 3 (ATF3) (
Hunt, Raivich, & Anderson, 2012
);
ATF3 being important for a variety of functions (
Rynes et al., 2012
). These
molecules are rapidly upregulated, probably depending on the retrograde
transport of JNK, with the purpose of both preserving neuronal survival as
well as inducing regeneration (
Lindwall, Dahlin, Lundborg, & Kanje,
2004; Lindwall & Kanje, 2005a
). STAT3 is also a survival-promoting factor
that is present in neurons by using alternative pathways. The activation and
compensatory mechanisms are complex, since there is a cross talk between
the various signal transection pathways, a phenomenon also seen in Schwann
cells (
M˚rtensson, 2012
). Induction of ATF3 may also differ between motor
and sensory neurons. The number of neurons that express ATF3 also declines
rapidly after an injury, particularly observed in dorsal root ganglia, that is, sen-
sory neurons, which is important when discussing the timing of nerve repair
and reconstruction. Thus, an early repair or reconstruction facilitates neuronal
survival. In addition, there seems to be a differential upregulation of ATF3
after injury in different types of sensory neurons since the upregulation of
ATF3 is particularly important for sensory neurons that project to the skin
Figure 7.1
—
Cont'd the growth cone and philopodia and the surrounding Schwann
cells during the regeneration which occur along important basal membrane that con-
tains laminin and fibronectin (B). In the growth cone actin filaments are assembled
depending on local signal transduction mechanisms that stir the direction of the out-
growing axons (C). Reproduced by kind permission of
Raivich and Makwana (2007)
.
