Actin Isoforms in Neuronal Development and Function - International Review of Cell and Molecular Biology - page 193

which also correlated with decreased axonal outgrowth in cultured DRG
neurons. It was inferred that the β-actin 3′ UTR-GFP construct can saturate
the cellular mRNA localization machinery (presumably ZBP1), and lead to
deficits in mRNA localization and local translation. It was further shown
that forced overexpression of ZBP1 could rescue this phenotype, suggest-
ing that ZBP1 may actually be a limiting factor in RNA localization and
axon outgrowth. Heterozygous ZBP1 mice express approximately 40% of
the ZBP1 mRNA found in wild-type littermates, and interestingly exhibit
similar axon outgrowth deficits as those observed in neurons expressing
the β-actin 3′ UTR-GFP construct as well as impaired sciatic nerve regen-
eration in vivo. Overexpression of β-actin does not rescue the effects of
limited ZBP1 availability, however, consistent with the finding that β-actin
is not required for functional nerve regeneration in vivo ( Cheever et al.,
2011 ). Thus, as noted above, ZBP1 likely plays an important role in neuro-
nal development and function but evidence suggesting that this function is
primarily through the localization of β-actin mRNA and protein in vivo
remains elusive. While the β-actin 3′ UTR and full length mRNA appear to
be ideal readouts for ZBP1 function, care should be taken in inferring that
this has direct physiological relevance in vivo.
6.3. Human Neurological Diseases Related to β - and γ -Actin
The specific contributions of actin isoforms to human neuronal function
and disease have only recently begun to receive attention. However, in the
last two decades, mutations in both genes encoding β- and γ-actin ( Actb and
Actg1 , respectively) have been identified in a small group of patients often
exhibiting neurological phenotypes. Broadening the search parameters of
human diseases to include conditions where an actin isoform is believed to
be specifically misregulated reveals the possible connection between β-actin
and the motor neuron disease spinal muscular atrophy (SMA). Implications
for actin isoform roles in these human conditions are described below.
6.3.1. Potential Role for β -Actin in Spinal Muscular Atrophy
SMA is the leading genetic cause of death in infants and the second most
common autosomal recessive disease in humans with an incidence of 1 in
10,000. Mutations in the survival motor neuron 1 gene ( SMN1 ) lead to
decreased levels of its encoded protein product SMN, resulting in the loss
of lower α-motor neurons, muscle atrophy, and in the most severe cases,
death ( Lefebvre et al., 1995 ; Lunn and Wang, 2008 ; Monani, 2005 ). SMN
is ubiquitously expressed with functions best understood in the biogenesis