Actin Isoforms in Neuronal Development and Function - International Review of Cell and Molecular Biology - page 197

( Rendtorff et al., 2006 ; van Wijk et al., 2003 ; Zhu et al., 2003 ). Although
there is a significant neurological component to the proper reception and
interpretation of sound, two pieces of evidence suggest that these mutations
may not specifically perturb neuronal function. The first is that Actg1 null
mice have been generated and fully characterized ( Belyantseva et al., 2009 ).
No neuronal or neurobehavioral phenotypes have been identified to date,
suggesting that γ-actin is not essential for neuronal development or func-
tion potentially due to overlapping functions with β-actin. The primary
pathological finding from Actg1 KO mice is the progressive loss of hair cell
stereocilia ( Belyantseva et al., 2009 ; Perrin et al., 2010 ), likely explaining the
progressive hearing loss experienced by these mice and the human patients.
Secondly, the hearing loss in human patients is nonsyndromic, indicating
that hearing loss is the only symptom reported and suggesting that gross
neuronal function is unperturbed.
One recent study, however, has identified Actg1 mutations in human
patients with neurological phenotypes, as well as three other distinct muta-
tions in Actb that cause the same genetic disorder, Baraitser-Winter Syn-
drome ( Riviere et al., 2012 ). In addition to nonneurological phenotypes
including facial abnormalities, patients with Baraitser-Winter syndrome
also exhibit lissencephaly, intellectual disabilities, and seizures suggesting a
strong neurological component to this disease. Similar to what was reported
for the two β-actin mutations described above, protein levels of the mutated
actin isoforms were not perturbed in cultured lymphoblastoid cell lines
derived from patients. Thus, here again missense mutations in the cytoplas-
mic actins likely cause disease by a gain-of-function or dominant negative
mechanism. It is tempting to conclude that since mutations in both β-
and γ-actin cause the same genetic disease that both genes have redundant
functions. However, because of the likely gain-of-function nature of these
mutations, it is difficult to discern the functions of the normal protein from
those processes perturbed following gain-of-function mutations. Neverthe-
less, this new study demonstrates that proper regulation and function of the
cytoplasmic actins is directly relevant to neurological function in humans.
7. FUTURE DIRECTIONS
For the first time, validated isoform-specific antibodies, biochemi-
cally relevant amounts of nearly pure actin isoform protein, and KO cell
culture and animal models are available for the study of actin isoforms in
neurobiology. Given how little is currently understood, and considering the