Actin Isoforms in Neuronal Development and Function - International Review of Cell and Molecular Biology - page 184

severe phenotypes relating to neuronal migration, axon guidance, and syn-
aptic function. In this section, we will discuss what has been learned from
a number of mouse models as well as human studies relating to the roles of
β- and γ-actin in neuronal development and function.
6.1. Novel Roles for β -Actin Revealed by a CNS-Specific
β -Actin Knockout Mouse
6.1.1. Contributions of β -Actin to Actin Isoform Expression within the
Brain
Ablation of an actin isoform has now been demonstrated in several dif-
ferent tissues and cell types, and intriguingly almost always results in the
maintenance of total actin levels by upregulation of alternative actin iso-
forms ( Belyantseva et al., 2009 ; Bunnell and Ervasti, 2010 ; Bunnell et al.,
2011 ; Cheever et al., 2012 ). Although whole-body Actb KO mice exhibit
early embryonic lethality ( Bunnell et al., 2011 ; Shawlot et al., 1998 ; Shmer-
ling et al., 2005 ), we found that β-actin was rapidly ablated in the brains
of CNS- Actb KO embryos while total actin levels were preserved dur-
ing development ( Cheever et al., 2012 ). The maintenance of total actin
levels was due to a modest upregulation of γ-actin and a significantly larger
increase in the more distantly related α-smooth actin. Why α-smooth actin
was upregulated to such a significant extent is not clear. α-smooth actin
mRNA contains no identifiable zipcode sequence, and the protein is classi-
cally used as a marker for myofibroblasts, which migrate into and facilitate
the closure of wound sites ( Darby et al., 1990 ). The amount of α-smooth
actin in a cell culture model of myofibroblasts has also been shown to be
directly proportional to the amount of traction force a cell is able to gener-
ate ( Chen et al., 2007 ; Hinz et al., 2002 ). It is thus tempting to speculate
that neurons may specifically upregulate α-smooth actin in the absence of
β-actin due to its cell traction producing properties, which would certainly
be useful for migrating neurons in vivo. Nevertheless, it also possible that
the ectopic expression of α-smooth actin is itself pathogenic and responsible
for some or all of the phenotypes observed in CNS- Actb KO mice. Future
studies with β-α-smooth actin double KO mice will be required to deter-
mine if the upregulation of α-smooth actin is compensatory, detrimental, or
has no effect. Additionally, β-γ-actin double KO mice could provide insight
into whether the upregulation of γ-actin is also functionally relevant.
The preservation of total actin levels during development may explain
why CNS- Actb KO embryos were morphologically indistinguishable from
controls at birth, although nearly two-thirds were still lost perinatally