Cis and trans RET signaling control the survival and central projection growth of rapidly adapting mechanoreceptors

RET can be activated in cis or trans by its co-receptors and ligands in vitro, but the physiological roles of trans signaling are unclear. Rapidly adapting (RA) mechanoreceptors in dorsal root ganglia (DRGs) express Ret and the co-receptor Gfra2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfra2 null mice display comparable early central projection deficits, but Gfra2 null RA mechanoreceptors recover later. Loss of Gfra1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfra1;Gfra2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRa1 produced by neighboring DRG neurons activates RET in RA mechanoreceptors. Taken together, our results suggest that trans and cis RET signaling could function in the same developmental process and that the availability of both forms of activation likely enhances but not diversifies outcomes of RET signaling.