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functions have been investigated and these findings are highlighted here and
in the following sections.
4.1. Transcriptional Regulation
As introduced above, nuclear functions of actin are increasingly being uncov-
ered with wide ranging effects on gene transcription and cellular function.
Specifically, research on the transcriptional regulator serum response factor
(SRF) has unveiled a potential role for actin isoforms in regulating their
own and other proteins expression. SRF binds to a sequence element called
the CArG box or serum response element that is present in the promoters
of all actin isoform genes as well as a large number of others ( Knoll and
Nordheim, 2009 ; Miano et al., 2007 ). SRF is believed to be constitutively
bound to these promoter elements but requires the binding of a coactivator
falling into the ternary complex factor (TCF) or myocardin-related tran-
scription factor (MRTF) families for full activity ( Kalita et al., 2012 ). The
regulation of these coactivators is thus critical for modulating SRF activity,
and appears to be controlled primarily by subcellular localization of these
factors as they shuttle in and out of the nucleus. The shuttling of MRTFs
is particularly relevant to this discussion as it is dependent on direct bind-
ing to monomeric, globular actin or G-actin ( Miralles et al., 2003 ). Work
in fibroblast cell lines has shown that in unstimulated conditions, MRTFs
are bound to G-actin, which both inhibits nuclear import and promotes
nuclear export of MRTFs, thus preventing activation of SRF and transcrip-
tion of target genes. When these cells are stimulated with various growth
factors, actin polymerization leads to the relative depletion of G-actin as
monomers are incorporated into filaments. This relieves the inhibition on
MRTFs nuclear import and leads to MRTFs binding SRF and the induc-
tion of transcription ( Vartiainen et al., 2007 ).
While much of the previous work on the SRF transcriptional pathway
was worked out in cell culture and striated muscle systems, a number of
recent studies have characterized neuronal and CNS roles for SRF. Ablation
of SRF in the forebrain leads to impaired neuronal migration in the rostral
migratory stream, corpus callosum agenesis ( Alberti et al., 2005 ), and defects
in the guidance of mossy fiber axons within the hippocampus ( Knoll et al.,
2006 ). These tissue defects correlated with impaired neurite outgrowth and
axon guidance in stripe assays with primary neurons cultured from these
same SRF KO mice ( Knoll et al., 2006 ). Immunostaining and RT-PCR
analysis revealed that SRF-deficient neurons had decreased levels of β-actin,
raising the possibility that decreased levels of this actin isoform contributed
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