Cell migration is an evolutionary conserved mechanism that underlies the development and functioning of
organisms (Tondeleir et al., 2009). Despite the differences in cell types involved, their migratory events occur
by similar molecular mechanisms that rely on a functional actin cytoskeleton. The actin system is complex and
there is reciprocal communication with the extracellular matrix and with other cells via various signaling
pathways. Due to this complexity, our research group initiated studying the actin cytoskeleton via systems
biology approaches. The model system we employ is the unique β-actin knock out (KO) mouse. One of the
surprising results is that deleting β-actin not only impairs cell migration but also causes reprogramming of the
expression profile of cells. Based on these recent data we formulate various hypotheses that will be addressed in
this project.
Genetic ablation of β-actin results in embryonic lethality at midgestation: day E10,5 (Schmerling et al., 2005).
Our primary observation is the actin isoform switch or compensatory expression of other actin isoforms
(mainly α-smooth muscle actin, αSMA) in the β-actin KO mouse embryonic fibroblasts (MEFs) and embryo’s.
In addition, β-actin KO MEFs display a severe migration defect and pronounced stress fiber and focal adhesion
formation, caused by a feedback mechanism induced by overproduction of αSMA and involving Rho-ROCK
activity. Disrupting the stress fibers with ROCK inhibitor or blebbistatin restores cell migration, indicating that
cell migration can occur without β-actin and challenging the dogma in the field that β-actin is the driving force
for cell migration (Lambrechts et al., in preparation). It also shows that the cell migration defect is a secondary
effect of β-actin ablation, due to altered regulation of the actin cytoskeleton. Consistent with this, quantitative
proteomics and micro-array experiments indicate dramatic changes in gene expressions (1580 affected genes)
between WT MEFs and β-actin KO MEFs. These observations strengthen our hypothesis that knock-out of β-
actin triggers αSMA expression, leading to altered cytoskeletal organization and/or subsequent
differential expression regulation.