Molecular Control of Axon Growth: Insights from Comparative Gene Profiling and High-Throughput Screening - International Review of Neurobiology - page 48

screening in C. elegans identified PKC ( Samara et al., 2010 ) and Dlk1
( Hammarlund et al., 2009 ), a member of the MAP kinase cascade, as
critical for axon growth; both of these molecules have also been
implicated in supporting axon growth in mammalian systems ( Eto et al.,
2010; Hirai et al., 2006; Toni, Stoppini, & Muller, 1997; Wu, Zheng,
McDonald, Chang, & Twiss, 2003 ). These results demonstrate
evolutionary conservation of gene function for axon growth and support
the idea that using invertebrate species as screening platforms will be a
viable means of identifying novel regeneration-associated genes.
4. PERIPHERAL VERSUS CENTRAL NERVOUS SYSTEM
4.1. Correlative and functional tests of gene function
The PNS is the most widely studied example of successful regeneration.
Dorsal root ganglion (DRG) neurons, motor neurons, and sympathetic neu-
rons are all capable of regenerating their peripherally projecting axons. The
regenerative capacity of PNS neurons is clearly higher than CNS neurons
and, for decades, has motivated efforts to understand its molecular basis
by comparing gene expression in regenerating PNS neurons to non-
regenerating controls. These controls have variously included uninjured
PNS neurons, injured CNS neurons, or DRG neurons injured in their cen-
trally projecting, nonregenerating axons. This basic strategy has changed
little in 30 years, but technical developments have advanced the field.
Starting with protein gel electrophoresis of peripheral axoplasm and accel-
erating with the spread of antibodies and molecular biology techniques in
the 1980s and 1990s, by the turn of the twenty-first century researchers
had identified nearly 100 genes whose expression correlated with injury
to PNS neurons (see Fernandes & Tetzlaff, 2002 for a comprehensive sur-
vey). Similar to embryonic and nonmammalian neurons, these genes span
functional categories, including adhesion receptors, structural proteins,
signaling molecules, neurotransmitters, guidance receptors, ion channels,
transcription factors, and others.
The extent to which the molecular mechanisms of PNS regeneration
overlap with those of embryonic axons is controversial ( Emery, Royo,
Fischer, Saatman, & McIntosh, 2003; Filbin, 2006; Hoffman, 2010; Zhou
& Snider, 2006 ). The processes clearly are not identical. In vitro ,
pharmacological blockade of key signaling pathways affects neurite length
from embryonic versus regenerating adult neurons very differently;
inhibitors of MAP kinase and PI3 kinase signaling block only embryonic