Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling
Cheng J., Sahani S., Hausrat TJ., Yang JW., Ji H., Schmarowski N., Endle H., Liu X., Li Y., Böttche R., Radyushkin K., Maric HM., Hoerder-Suabedissen A., Molnár Z., Prouvot PH., Trimbuch T., Ninnemann O., Huai J., Fan W., Visentin B., Sabbadini R., Strømgaard K., Stroh A., Luhmann HJ., Kneussel M., Nitsch R., Vogt J.
Precise connection of thalamic barreloids with their corresponding cortical barrels is critical for processing of vibrissal sensory information. Here, we show that PRG-2, a phospholipid-interacting molecule, is important for thalamocortical axon guidance. Developing thalamocortical fibers both in PRG-2 full knockout (KO) and in thalamus-specific KO mice prematurely entered the cortical plate, eventually innervating non-corresponding barrels. This misrouting relied on lost axonal sensitivity toward lysophosphatidic acid (LPA), which failed to repel PRG-2-deficient thalamocortical fibers. PRG-2 electroporation in the PRG-2(-/-) thalamus restored the aberrant cortical innervation. We identified radixin as a PRG-2 interaction partner and showed that radixin accumulation in growth cones and its LPA-dependent phosphorylation depend on its binding to specific regions within the C-terminal region of PRG-2. In vivo recordings and whisker-specific behavioral tests demonstrated sensory discrimination deficits in PRG-2(-/-) animals. Our data show that bioactive phospholipids and PRG-2 are critical for guiding thalamic axons to their proper cortical targets.