Precise somatotopic thalamocortical axon guidance depends on LPA-mediated PRG-2/Radixin signaling
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Abstract
The function of the nervous system relies to the precision of axon wiring. During embryonic brain development, thalamocortical axons (TCAs) navigate through the ventral telencephalon to reach the intermediate zone (IZ) of the cerebral cortex. TCAs wait in the IZ until the late embryonic stage before they start to innervate the cortical plate (CP) and to form connections with layer IV neurons.
This study discovered that the plasticity related gene protein 2 (PRG-2), which is expressed at TCAs, is critically important to maintain TCAs in the IZ and prevents a premature and aberrant entrance of TCA into the CP at the early embryonic day 16 (E16). To explore the underlying molecular mechanism, TCAs growth behaviors are observed in vitro cultures. TCAs show a repulsive response to lysophosphatidic acid (LPA) via PRG-2 present in their growth cones (GCs). However, PRG-2 knock-out fibers lose sensitivity to the guidance cue LPA, which is produced by the subplate-secreted autotaxin (ATX) in developing brains. The results suggest that subplate neurons play a major role in the guidance of TCAs development.
Further signaling pathway research shows that PRG-2 interacts with Radixin (RDX) and mediates RDX phosphorylation upon LPA-stimulation. Consequently, PRG-2/pRDX axis coordinates actin cytoskeleton changes in GCs of thalamocortical axons in response to LPA. In sum, precise somatotopic termination of TCAs critically depends on LPA-mediated PRG-2/RDX signaling.