Abstract
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 Gfrα2 and depend on Ret for survival and central projection growth. Here, we show that Ret and Gfrα2 null mice display comparable early central projection deficits, but Gfrα2 null RA mechanoreceptors recover later. Loss of Gfrα1, the co-receptor implicated in activating RET in trans, causes no significant central projection or cell survival deficit, but Gfrα1;Gfrα2 double nulls phenocopy Ret nulls. Finally, we demonstrate that GFRα1 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.
Highlights
The neurotrophic receptor tyrosine kinase RET plays critical roles in many biological processes, including kidney genesis, spermatogenesis, and development of enteric, sensory, autonomic, and motor neurons (Runeberg-Roos and Saarma, 2007; Iban ̃ez, 2013)
Since RET can be activated by GFLs/GDNF family receptor alpha (GFRa) either in cis or in trans in vitro, we asked if the expression patterns of Gfra1, Gfra2, Gdnf, and Nrtn in the developing spinal cord (SC) and DRGs would provide insight into RET signaling in Rapidly adapting (RA) mechanoreceptors in vivo
We found that the RA mechanosensory central projection deficit is negligible in postnatal Gfra2 and Nrtn mutant mice
Summary
The neurotrophic receptor tyrosine kinase RET plays critical roles in many biological processes, including kidney genesis, spermatogenesis, and development of enteric, sensory, autonomic, and motor neurons (Runeberg-Roos and Saarma, 2007; Iban ̃ez, 2013). Loss of RET signaling leads to Hirschprung’s disease, while RET gain of function has been implicated in various human carcinomas (Runeberg-Roos and Saarma, 2007; Santoro and Carlomagno, 2013). RET is the common signaling receptor for the glial cell line-derived neurotrophic factor (GDNF) family of ligands (GFLs), which includes GDNF, neurturin (NRTN), artemin, and persephin. For RET activation and signaling, GFLs first bind to a GPI-linked GDNF family receptor alpha (GFRa), which associates with RET to form an active signaling complex (Airaksinen and Saarma, 2002). The GFRas and their high-affinity ligand pairs are GFRa1 and GDNF (Jing et al, 1996; Treanor et al, 1996), GFRa2 and NRTN (Baloh et al, 1997; Buj-Bello et al, 1997; Klein et al, 1997), GFRa3 and artemin (Baloh et al, 1998), and GFRa4 and persephin (Yang et al, 2007)
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