Biology Reference
In-Depth Information
Using multiple different shRNA vectors to knock down ZBP1 expression,
it was found that ZBP1 appears to be required for the development but
not maintenance of dendritic branches ( Perycz et al., 2011 ). This effect was
dependent on the RNA-binding and Src-mediated derepression functions
of ZBP1, strongly suggesting that localization of ZBP1 target mRNAs is
critical for proper dendritic arborization. These authors then proceeded to
examine the distribution of β-actin mRNA and protein within control
and ZBP1 knockdown neurons. They found that β-actin levels decreased
significantly only in distal, but not proximal dendrites, providing support
for the hypothesis that local translation of proteins and specifically actin is
most crucial at large distances from the neuronal cell body. Overexpression
of β-actin partially rescued the decreased dendritic branching phenotype in
ZBP1 knockdown neurons, although by what mechanism and if the zip-
code sequence was included in the vector were not clear. These results are
also consistent with what has been observed in β-actin-deficient primary
hippocampal neurons. Although not statistically significant, β-actin KO
neurons also showed a trend of decreased dendritic branching at a much
earlier timepoint in culture ( Cheever et al., 2012 ). Interestingly, overexpres-
sion of microtubule-associated protein 2 (MAP2) also rescued some of the
phenotypes associated with ZBP1 knockdown, suggesting that impaired
localization of β-actin may not be exclusively responsible for the simplified
dendritic branching ( Perycz et al., 2011 ). Further work will be required in
order to determine if β-actin is definitively involved in dendritic morphol-
ogy, or perhaps merely a bystander.
Beginning at roughly the same time as dendritic arbor maturation, filo-
podia strung along the length of dendrites begin to form, elongate, and
retract in an apparent stochastic nature ( Holtmaat and Svoboda, 2009 ;
Hotulainen and Hoogenraad, 2010 ; Yoshihara et al., 2009 ). However, when
these filopodia encounter an axon, they can become stabilized most likely
due to electrical or trophic signals, which elicit a stabilization of the under-
lying actin cytoskeleton ( Shimada et al., 1998 ; Tiruchinapalli et al., 2003 ).
Further increases in actin polymerization can result in the tip of the filo-
podia expanding, creating a mushroom-like morphology characteristic of
a mature dendritic spine, the site of the majority of excitatory synapses in
the mammalian brain ( Honkura et al., 2008 ; Hotulainen and Hoogenraad,
2010 ; Okamoto et al., 2004 ). With an ever increasing number of studies
identifying perturbed numbers or morphology of dendritic spines in vari-
ous neurodegenerative and neurodevelopmental disorders ( Fiala et al., 2002 ;
Penzes et al., 2011 ), the mechanisms by which dendritic spines are formed is
Search WWH ::




Custom Search