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difficulties in drug delivery, maintenance of constant neurotrophic factor
concentrations, and the comorbidities associated with achieving these aims.
Moreover, the availability of conditional knockout mice whose muta-
tions can be targeted both spatially and temporally obviate the problem that
some homozygous knockout mice can be embryonically lethal, thus limiting
their usefulness. In addition, emerging tools include mice the axons or
Schwann cells of which express fluorescent chromophores, which enabled
new experiments with direct visualization of nerve regeneration over time.
In the past years, many studies of peripheral nerve regeneration have used
knockout animals to elucidate the role of different neurotrophic factors dur-
ing the process. For example, it has been shown that animals lacking CNTF
are unable to produce motor nerve terminal sprouts after nerve transection
or botulinum toxin injection and have also decreased ability to repair
peripheral nerve damage from crush injury ( Mizisin, Vu, Shuff, &
Calcutt, 2004 ). Studies using GDNF-deficient mice, as well as NT-3 defi-
cient mice, revealed inadequate development of sympathetic and sensory
neurons ( Anand, 2004 ), whereas knockout animals for the low-affinity
NGF receptor p75NGFR showed decreased sensory innervation ( Lee
et al., 1992 ). Transgenic mice lacking IGF-1 show a decrease in motor
and sensory nerve conduction velocities but no significant reduction in
peripheral nerve myelination ( Gao et al., 1998 ).
Animals lacking ApoD revealed a decrease in motor nerve conduction
velocity and thickness of myelin sheath in intact nerves, and after injury, axon
regeneration and remyelination are delayed ( Ganfornina et al., 2010 ). The
lack of Cx32, a gap junction protein, showed abnormally thinmyelin sheaths,
reflecting myelin degeneration-induced Schwann cell proliferation, while
nerve conductance properties are altered only slightly ( Anzini et al., 1997 ).
Neuropilin-2-deficient mice showed slower axonal regeneration,
remyelination of the regenerating axons, and recovery of normal gait after
a crush lesion of the sciatic nerve ( Bannerman et al., 2008 ). An experiment
using the Cre-loxP system to disrupt the laminin g 1gene in Schwann cells
showed that, during development, Schwann cells that lack laminin g 1 were
unable to differentiate and synthesizemyelin proteins, and therefore unable to
myelinate axons. Moreover, after sciatic nerve crush, the axons showed
impaired regeneration inmutant mice ( Chen & Strickland, 2003 ). Peripheral
nerves develop and function normally in GFAP-null mice. However, axonal
regeneration after crush lesion was delayed. Mutant Schwann cells
maintained the ability to dedifferentiate but showed defective proliferation,
a key event for successful nerve regeneration ( Triolo et al., 2006 ).
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