Precise Somatotopic Thalamocortical Axon Guidance Depends on LPA-Mediated PRG-2/Radixin Signaling

Abstract

SummaryPrecise 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.

The Axonal Membrane Protein PRG2 Inhibits PTEN and Directs Growth to Branches

“…Its periodic localization, revealed by super-resolution is controlled by axonal F-actin, as suggested by latrunculin experiments. Second, PRG2 has recently been found to interact with, and to activate, radixin (Cheng et al., 2016). Radixin, an ERM family protein, crosslinks F-actin to the plasma membrane and has been shown to stabilize membrane protrusions in neuronal growth cones (Menon and Gupton, 2016).…”

“…Radixin, an ERM family protein, crosslinks F-actin to the plasma membrane and has been shown to stabilize membrane protrusions in neuronal growth cones (Menon and Gupton, 2016). Although the PRG2-radixin interaction was studied in the context of lysophosphatidic acid (LPA)-induced growth cone guidance in thalamocortical neurons (Cheng et al., 2016), it is possible that a similar mechanism may operate along the axon shaft. Indeed, our live cell imaging identified F-actin rearrangements—specifically during the formation of filopodia—to occur preferentially in the vicinity of PRG2 clusters along the axon.…”

“…Its periodic localization, revealed by super-resolution is controlled by axonal F-actin, as suggested by latrunculin experiments. Second, PRG2 has recently been found to interact with, and to activate, radixin (Cheng et al, 2016).…”

Where does axon guidance lead us?

“…For instance, lyso-phosphatidyl-Β-D-glucoside, a glycerophospholipid, has been identified as a subpopulation-specific guidance cue for sensory afferents in the dorsal spinal cord 54 . PRG2/Lppr3 (plasticity-regulated gene-2), a molecule interacting with lysophosphatic acid, was shown to regulate guidance of thalamocortical axons 55 . But clearly, the focus in axon guidance research today is on the characterization of regulatory mechanisms.…”

Cornu Ammonis Regions–Antecedents of Cortical Layers?

“…As L4 and its thalamic inputs mature postnatally, spiny stellate cells receive a transient input from SOM interneurones in L5b, which themselves receive thalamic input. Development of thalamic input to spiny stellates is delayed in the absence of this transient input (Marques-Smith et al, 2016 ), while thalamic afferents are misdirected to inappropriate barrels when Proteoglycan-2 (PRG-1, a phospholipid- interacting molecule) is knocked out (Cheng et al, 2016 ).…”