Lrig1 and Lrig3 cooperate to control Ret-mediated axonal growth of sensory neurons and nonpeptidergic epidermis innervation.

DE VINCENTI, ANA PAULA; HEDMAN, HAKAN; ALSINA, FERNANDO; LEDDA, FERNANDA; FERRERO RESTELLI, FACUNDO; PARATCHA, GUSTAVO

Buenos Aires

Congreso; LASDB Meeting 2019 Xth Meeting of the Latin American Society for Developmental Biology; 2019

Latin American Society for Developmental Biology

In previous work, we demonstrated that Lrig1, a transmembrane protein containing leucine-rich repeats and Ig-like domains in its extracellular region, directly interacts with the GDNF receptor Ret and inhibits ligand-induced Ret signaling acting through negative feedback-loop. This observation prompted us to examine whether other Lrig family members such as Lrig2 and Lrig3 could also regulate GDNF/Ret signaling. We found that Lrig2 and Lrig3 physically associate with Ret and their interaction inhibits its autophosphorylation. We also observed that Lrig family members are co-expressed with Ret in developing DRG sensory neurons; being Lrig1 and Lrig3 the two most highly co-localized ones. Moreover, treatment of primary cultures of DRG neurons with GDNF ligands induces a significant increase in the expression of Lrig1 and Lrig3. In vitro analysis of Lrig1/Lrig3-deficient neurons shows potentiation of axonal growth in response to GDNF ligands. Finally, to gain insights into Lrig function in vivo, we studied the epidermis innervation of nonpeptidergic axons and thermal nociception, two events critically regulated by Ret signaling. We observed that Lrig1 and Lrig3 act redundantly to ensure proper cutaneous innervation of nonpeptidergic axons and behavioral sensitivity to cold. Together our findings provide novel insights into the physiological contribution through which Lrig genes control neuronal morphology, connectivity and function.