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

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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.

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Michael S Fleming

Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Anna Vysochan

Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Sόnia Paixão

Molecules - Signals - Development, Max Planck Institute of Neurobiology, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Jingwen Niu

Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

Competing interests
The authors declare that no competing interests exist.
Rüdiger Klein

Molecules - Signals - Development, Max Planck Institute of Neurobiology, Martinsried, Germany

Competing interests
The authors declare that no competing interests exist.
Joseph M Savitt

Parkinson's Disease and Movement Disorder Center of Maryland, Elkridge, United States

Competing interests
The authors declare that no competing interests exist.
Wenqin Luo

Department of Neuroscience, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States

For correspondence
luow@mail.med.upenn.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

Animal experimentation: Mice except GDNFlacZ line were raised in a barrier facility in Hill Pavilion, the618 University of Pennsylvania. All procedures were conducted according to animal protocols619 approved by Institutional Animal Care and Use Committee (IACUC) of the University of620 Pennsylvania and National Institutes of Health guidelines. GDNFlacZ mice were raised in621 accordance with the European Community Council Directive of November 24, 1986622 (86/609/EEC), and approved by the ethics.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.