Biology Reference
In-Depth Information
vertebrates that can regenerate axons in the adult do not display dispropor-
tionately more axon growth during development than mammals, which lack
regenerative capacity in the adult CNS (
Tanaka & Ferretti, 2009
). Thus, the
in vitro
data may point to a role for 5-HT in modulating CNS regenerative
capacity, and will require addressing this question in an appropriate model
system, for example, optic nerve crush or spinal cord injury animal models.
A number of possible explanations exist for the discrepancy between
in vitro
and
in vivo
data. First, modulation of signaling through developmen-
tally regulated cofactors whether from blood or confined to the extracellular
matrix (ECM) could interfere with 5-HT-stimulated or -suppressed neurite
growth. ECM molecules such as myelin-associated glycoproteins (see
Volume 106 Chapter 3) are known to inhibit axon regeneration in mature
CNS (
Yiu & He, 2006
). Either those or other 5-HT pathway-specific mol-
ecules may hinder neurite growth effects of 5-HT
in vivo
. Studying 5-HT's
in vivo
role in neurite growth in animal models that combine manipulations
of 5-HT with other such molecules could help dissect mechanisms of 5-HT
effects in multiple systems, and further effort is needed to identify potential
modulators of 5-HT pathways which affect neurite growth.
Second, downstream mechanisms through which 5-HT receptor sub-
types regulate neurite growth remain elusive. Pathways downstream G pro-
tein subunits, Ca
2
รพ
dynamics, membrane polarization, Rho GTPases
activities, mitochondrial transport, cytoskeletal rearrangements, growth fac-
tors regulation, and gene transcription, are all potential effectors as discussed
earlier. The molecular pathways through which different 5-HT receptor
subtypes regulate neurite growth may involve cross talk and converge on
shared targets; alternatively, they may act synergistically. Deciphering such
molecular mechanisms and establishing their dominance in relation to var-
ious 5-HT-related phenotypes, including neurite growth, are important for
several disciplines in biological sciences.
Third, developmental compensatory mechanisms and redundancy in
5-HT receptor functions may be another reason why knockout of a single
5-HT receptor subtype may not demonstrate axon growth-related pheno-
types. Double-knockout animal models and conditional acute knockout
using viral delivery of Cre-recombinase into transgenic mice with a floxed
gene(s), or knockdown using shRNA approaches, could help address these
limitations. Developmental compensatory mechanisms at the level of down-
or upstream pathways also pose potential limitations which would be chal-
lenging to address experimentally. Depleting 5-HT levels in the CNS should
reduce receptors' activity, but these receptors' basal activity may be sufficient
