Biology Reference
In-Depth Information
(
Udo et al., 2005
), axonal transport of mitochondria, and tubulin acetylation
(
Chen, Owens, Makarenkova, & Edelman, 2010
)—all of which have been
implicated in neurite growth. 5-HT can also modulate histone deacetylase 6
(
Chen et al., 2010
), which in turn could translocate to the nucleus and epi-
genetically regulate transcription; epigenetic mechanisms also have been
established as regulators of axon growth (
Trakhtenberg & Goldberg,
2012
). Expression of specific genes also could occur through 5-HT's regu-
lation of pathways which lead to direct activation of specific transcription
factors, for example, STAT3 in the case of Htr1A (
Fricker et al., 2005
);
STAT3 activation is known to increase axon growth (
Bareyre et al.,
2011
; see Volume 105 Chapter 7). 5-HT might also modulate expression
or activity of growth factors, for example, brain-derived neurotrophic factor
(
Vaidya, Marek, Aghajanian, & Duman, 1997; Zetterstr¨m et al., 1999
),
which could affect neurite growth in autocrine manner or through other
cells. Long-term effects of 5-HT on neurite growth through regulation of
gene transcription remain essentially unexplored. A particularly intriguing
element of 5-HT receptor biology arises from data suggesting that the
receptors may exhibit considerable basal levels of activity (
Barker,
Westphal, Schmidt, & Sanders-Bush, 1994
) even in the absence of 5-HT
stimulation. Studies using agonists, inverse agonists, and genetic
manipulations will have to be interpreted carefully in this context.
5. DISCUSSION
There has thus been an accumulation of
in vitro
evidence on the effects
of 5-HT on neurite growth in nonmammalian as well as mammalian CNS,
implicating receptor-specific signaling and demonstrating that the effects
vary depending on the receptor subtypes and neuronal type (
Table 4.1
).
Nevertheless, transgenic mouse models altering 5-HT levels or knocking-
out receptor subtypes have not revealed major developmental abnormalities
in axon growth, with an exception of the retinogeniculate and
thalamocortical projections' guidance and patterning, and fine dendritic
phenotypes identified in Htr3 knockout mice. However, the mechanisms
controlling developmental axon growth may be different from those regu-
lating axon regeneration in the mature CNS, and the latter may assume a role
of gate-keeping the developmental axon growth mechanisms as CNS ma-
tures. For example, although conditional knockout of Klf4 in retinal gan-
glion cells did not affect developmental axon growth, its absence resulted
in enhanced regenerative capacity (
Moore et al., 2009
). Certainly, lower
