Biology Reference
In-Depth Information
neurotransmission associated with reduced axon caliber as opposed to de-
fect in regeneration per se ( Tomita et al., 2006 ). siRNA-mediated knock-
down of Ndel1, a cytoskeletal interacting protein, was reported to suppress
peripheral regeneration, although axon counts were not provided ( Toth
et al., 2008 ). shRNA-mediated knockdown of Mst3b, a kinase involved
in MAPK signaling, reduced by 85% the number of axons regenerating
in the crushed radial nerve 3 days after injury ( Lorber, Howe, Benowitz, &
Irwin, 2009 ). The Mst3b effect is dramatic, but because longer time points
were not reported, it remains unclear whether this effect is permanent,
or whether it reflects a delay in the onset or speed of regeneration. At
the transcriptional level, nervous system-specific deletion of the transcrip-
tion factor c-Jun reduced the number of regenerating facial motor neurons
by approximately two thirds ( Raivich et al., 2004; Ruff et al., 2012 ). siRNA
directed against Sox11 reduced the speed of peripheral regeneration, possibly
by blocking the upregulation of Atf3, an established regulator of peripheral
regeneration ( Jankowski et al., 2009; Seijffers, Mills, & Woolf, 2007 ).
Overall, at least two general conclusions emerge from these tests of
requirement in PNS regeneration. First, as might be expected, the disruptive
effects of such disparate gene manipulations again support the notion that
regeneration depends on multiple cellular processes, from adhesion to
appropriate intracellular signaling to transcriptional control. Second, it is
interesting to note that, especially at later time points, deletion of any one
gene produces effects that are partial or even undetectable. Reminiscent
of gene knockout studies of developmental axon growth, this finding hints
that peripheral regeneration is robust in the sense of possessing redundancy
in essential genes or pathways.
The second category of functional experiments, perhaps more directly
aligned with therapeutic goals, tests whether genes associated with PNS
regeneration have the ability to enhance axon growth. Some studies attempt
to improve peripheral regeneration, which, despite its superiority to the
CNS, remains suboptimal in its speed and degree of participation by all neu-
rons ( Brown & Hardman, 1987; Witzel, Rohde, & Brushart, 2005 ). Two
recent experiments found that siRNA-mediated knockdown of Pten or
genetic knockdown of Tsc2, a negative regulator of mTOR activity,
increases the number of axons and/or speed of their regeneration in the
sciatic nerve ( Abe, Borson, Gambello, Wang, & Cavalli, 2010; Christie,
Webber, Martinez, Singh, & Zochodne, 2010 ). Overexpression of the
transcription factor Atf3 increased the speed of sciatic nerve regeneration
( Seijffers et al., 2007 ). These studies establish Atf3 as a positive regulator,
Search WWH ::




Custom Search