Controlling GDNF-Ret signaling by Lrig family members

ALSINA FC; FONTANET PA; HITA FJ; LEDDA F; PARATCHA G

San Diego

Congreso; 43rd Annual Meeting Society for Neuroscience 2013; 2013

Society for Neuroscience (SfN)

Glial cell line-derived neurotrophic factor (GDNF) is a soluble ligand that has potent trophic effects on ventral midbrain dopaminergic, motor, sensory, and sympathetic neurons. GDNF binds GFRα1 and recruits the receptor tyrosine kinase Ret into lipid rafts, leading to activation of downstream signaling pathways. The molecular mechanisms that restrict Ret activation are not well understood. In a previous work, we demonstrated that Lrig1, a transmembrane protein containing leucine-rich repeats and Ig-like domains in its extracellular region, directly interacts with Ret and negatively regulates GDNF-Ret signaling through inhibition of GDNF binding to the Ret complex and recruitment of Ret to lipid rafts (Ledda et. al., 2008). This observation prompted us to examine whether other Lrig family members such as Lrig2 and Lrig3 could also regulate GDNF-Ret signaling. Here, we report that Lrig2 and Lrig3 are co-expressed with Ret in many developing DRG sensory neurons. Interestingly, Lrig2 and Lrig3 are capable of physically associate with Ret and their interaction inhibits GDNF-dependent Ret receptor autophosphorylation and mitogen-activated protein kinase (MAPK) activation in response to GDNF. In neuronal cells, Lrig2 and Lrig3 overexpression also restrict GDNF-Ret-induced neurite outgrowth in a cell-autonomous manner. Taken together, our findings demonstrate that Lrig members form complexes with Ret and support a model in which Lrig family members might cooperate to restrict GDNF signaling in different Ret-positive neuronal types.