| Abstract |
The development of bilateral organized organisms requires the formation of complicated neuronal
circuits, in order for the coordinated movements to be achieved. Commissural axons play a major
role in this formation, with the developing spinal cord (SC) being a great model for their study.
Commissural neurons extend very long commissural axons, which respond to a great variety of
guidance cues, cross the midline and project contralaterally. The main structure that is necessary
for commissural axons to navigate towards their targets is the growth cone, which carries a lot of
guidance receptors and is full of actin filaments, thus exhibiting great motility. In order to respond
rapidly to extracellular signals, growth cones require some sort of signaling autonomy from the
cell body. A key process to this autonomous signaling is local translation, namely the ability of
axons to synthesize in situ their proteins of need, from a pool of free ribosomes and cytosolic
mRNAs found in axons. Although local translation is pivotal for axon development and numerous
guidance signals require de novo protein synthesis, very little is known up to date about its
regulation and its coordination with the cytoskeleton. A recent study in the developing mouse brain
revealed that a protein called Mena displays dual functions in the regulation of actin filaments (as
previously described) and local translation in axons. More specifically, Mena forms a novel
ribonucleoprotein complex (Mena-RNP) through its interaction with known RNA-binding
proteins (RBPs), such as the Heterogeneous Nuclear Ribonucleoprotein K (hnRNPK) and
Poly(RC) Binding Protein 1 (PCBP1), and cytosolic mRNAs. Mena is necessary for the axonal
local translation of the mRNAs in the complex, both under steady-state conditions and downstream
of growth factors. Furthermore, previous studies have shown that Mena-deficient mice exhibit
numerous defects in the development of their nervous system, including the formation of neuronal
commissures of the brain and SC. However, the molecular basis of the observed phenotypes and
their association with the dual function of Mena remains elusive.
In order to gain understanding into the mechanistic aspects of the Mena-knockout phenotypes, we
wanted to examine the function of the protein in the developing SC, and elucidate its potential role
in axon guidance via local translation regulation. We first tested the expression pattern of Mena in
the developing SC, and subsequently tested the conservation of the interactions between Mena and
translation regulating RBPs, like hnRNPK and PCBP1, as well as cytosolic mRNAs. Such
conservations would indicate a role for Mena in local translation regulation, similar to the one
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found in the developing brain, and would nicely agree with the observed commissural axons
phenotype in Mena-KO mice. Our results did not confirm the conservation of the Mena-RNP
complex, which implies that: a) Mena does not form such a RNP complex in the SC, b) Mena
forms a different RNP with tissue-specific components in the SC, or c) Mena may only function
via actin regulation in the particular axonal populations of the SC. These possibilities need to be
further tested in additional future studies, in order to understand the role of Mena in axon
development.
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