CELL BIOLOGY OF THE NEURON Polarity ... - Tavernarakis Lab

Cell Biology of the Neuron: Polarity, Plasticity and Regeneration, Crete 2011
Molecular Dissection of EphA4-Mediated Signaling
Christine Hassler, Rüdiger Klein
Max-Planck-Institute for Neurobiology
In the developing nervous system, Eph receptor tyrosine kinases (Ephs) and their
ephrin ligands act as a contact-dependent and bidirectional signaling system,
since both receptors and ligands are cell-surface tethered and can signal into their
respective cells. The Eph-ephrin system plays prominent roles during axon
guidance ranging from the regulation of midline crossing decisions to the
establishment of topographic maps.
We are currently analyzing, under physiological conditions, the signaling
requirements of two non-catalytic modules in the cytoplasmic region of EphA4,
the SAM domain and PDZ-binding-motif (PBM). No in vivo functions have so
far been assigned to these modules, although they are highly conserved among
Ephs across phyla. We have established a knock-in mouse line expressing an
EphA4 isoform lacking SAM+PBM (EphA4 ∆SP), but retaining full kinase
activity, and will be comparing EphA4 ∆SP mice to existing lines expressing
wild-type EphA4 or kinase-inactive EphA4 containing SP. Our main questions
are: Are the SP modules required for, or modulating, EphA4 signaling in some
developmental contexts, but not others? What is the effect of SP depletion on the
cell biology of neurons? In particular, is this region required for various EphA4dependent
axon guidance decisions?
So far, our analysis revealed two potentially interesting results: First, we find that
EphA4 ∆SP mice do not display defects in axon guidance of the thalamocortical
system. This suggests that the EphA4 ∆SP isoform can still respond to a gradient
of EphrinA5 in the cortex and mediate the development of a normal topography.
Second, EphA4 ∆SP mice display defects in formation of the dorsal funiculus, a
white matter structure in the spinal cord containing corticospinal tract (CST)
axons. CST axon guidance has previously been shown by us and others to require
functional EphA4 receptors. Although the exact role of EphA4 in formation of
the dorsal funiculus is unknown, it is likely that EphA4 controls wiring across the
midline which expresses ephrins. We speculate that EphA4's SP region is not
required for EphA4-dependent topographic mapping, but may modulate the
behavior of cells and their axons towards the spinal cord midline.
Presented by: Hassler, Christine
127
Poster No 045
Blue Session