Actin Isoforms in Neuronal Development and Function - International Review of Cell and Molecular Biology - page 163

to the axonal phenotypes observed. However, overexpression of full length
β-actin only moderately increased neurite length in cultured neurons, sug-
gesting that deficient levels of β-actin are not exclusively responsible for the
axonal phenotypes observed ( Knoll et al., 2006 ). Beyond the development
of the nervous system, additional SRF KO mouse models presented with
hyperactivity ( Parkitna et al., 2010 ) while others exhibited defects in learn-
ing and memory ( Etkin et al., 2006 ). Given that these behavioral pheno-
types are likely rooted in impaired synaptic transmission or plasticity, both
of which involve actin dynamics at the pre- and post-synapse, it remains
possible that the misregulation of actin isoforms may contribute at least
partially to the phenotypes reported in these animals.
The CNS roles for SRF may be particularly relevant to the function
of actin isoforms for two reasons. First, it was recently shown in mouse
embryonic fibroblasts that ablation of β-actin but not γ-actin disrupted
the polymerized or filamentous (F) actin to G-actin ratio, leading to pro-
found changes in gene expression including some SRF targets ( Bunnell
and Ervasti, 2010 ; Bunnell et al., 2011 ). It was thus proposed that β-actin
may specifically regulate the F- to G-actin ratio in cells, which is critical for
modulating the localization of MRTFs and SRF activation. It is currently
unknown but entirely plausible that β-actin may also perform a similar func-
tion in regulating the F- to G-actin ratio in neurons as well. Additionally,
work in mouse models ablated for β-actin in neurons revealed a number of
phenotypes including corpus callosum agenesis, hyperactivity, and memory
defects ( Cheever et al., 2012 ) that closely mimic those of SRF-deficient
mouse models (see Section 6.1 for more detailed discussion). Further work
will be required to definitively demonstrate that the phenotypes observed
in β-actin-deficient mouse models are mediated by SRF disruption, yet the
potential for modulating a large array of genes by perturbing a specific actin
isoform is an intriguing idea with significant therapeutic potential.
4.2. Posttranscriptional Regulation
The posttranscriptional regulation of β-actin has been intensively studied
and remains one of the most well-characterized aspects of actin isoform
biology. As described above, early studies in fibroblasts reported that β-actin
mRNA and protein were specifically enriched at the leading edge of motile
cells, which was not observed for γ- or α-actin isoforms ( Hill and Gun-
ning, 1993 ; Kislauskis et al., 1993 ). Work primarily from the laboratory of
Robert Singer described a mechanism where the specific localization of
β-actin was based on a 54 nucleotide sequence in the 3′ untranslated region