Retrograde Ret signaling controls sensory pioneer axon outgrowth

Abstract

The trafficking mechanisms and transcriptional targets downstream of long-range neurotrophic factor ligand/receptor signaling that promote axon growth are incompletely understood. Zebrafish carrying a null mutation in a neurotrophic factor receptor, Ret, displayed defects in peripheral sensory axon growth cone morphology and dynamics. Ret receptor was highly enriched in sensory pioneer neurons and Ret51 isoform was required for pioneer axon outgrowth. Loss-of-function of a cargo adaptor, Jip3, partially phenocopied Ret axonal defects, led to accumulation of activated Ret in pioneer growth cones, and reduced retrograde Ret51 transport. Jip3 and Ret51 were also retrogradely co-transported, ultimately suggesting Jip3 is a retrograde adapter of active Ret51. Finally, loss of Ret reduced transcription and growth cone localization of Myosin-X, an initiator of filopodial formation. These results show a specific role for Ret51 in pioneer axon growth, and suggest a critical role for long-range retrograde Ret signaling in regulating growth cone dynamics through downstream transcriptional changes.

A nuclear role for ARGONAUTE-2 in regulation of neuronal alternative polyadenylation

“…RET, the receptor for the neurotrophic factor GDNF, is expressed in the developing and in the mature nervous systems, and is important for axonal growth and synapse development (Baudet et al, 2008;Bonanomi et al, 2012;Enomoto et al, 2001;Gould et al, 2008;Honma et al, 2010;Kramer et al, 2006;Pachnis et al, 1993;Tuttle et al, 2019), including the neuromuscular junction (Baudet et al, 2008). The formation of the short and long versions of RET protein, RET9 and RET51, seems to be the translational consequence of the two alternative mRNA isoforms, downstream of AGO2 activity.…”

“…The secreted glial cell derived neurotrophic factor (GDNF) drives neurotrophic signaling that is important for axonal outgrowth, synapse maturation and neuron survival (Airaksinen & Saarma, 2002;Baudet et al, 2008;Bonanomi et al, 2012;Enomoto et al, 2001;Honma et al, 2010;Kramer et al, 2006;Pachnis et al, 1993;Runeberg-Roos & Saarma, 2007;Tuttle et al, 2019). Ret proto-oncogene is a tyrosine kinase receptor for GDNF (Romei et al, 2016) that is highly expressed in motor neurons (Baudet et al, 2008;Cintron-Colon et al, 2020;Pachnis et al, 1993).…”

Follicle-innervating Aδ-low threshold mechanoreceptors organize through a population-dependent mechanism

“…In vertebrates, early extending axons often act as a permissive substrate upon which later-born neurons can extend their axons, but the necessity of these early-extending axons is less clear (Melançon et al, 1997; Pike et al, 1992; Pittman et al, 2008). In an interesting parallel, Ret is expressed in both early-born Aβ RA-LTMRs and in a population of pioneer axons in the zebrafish posterior lateral line (Tuttle et al, 2019). Future studies will be required to determine if early born Ret + Aβ RA- LTMRs function as pioneers in the mouse DRG.…”

Transparent Touch: Insights From Model Systems on Epidermal Control of Somatosensory Innervation

“…Mav exerts short and long-range effects on C4da dendrite growth, yet Mav exhibits limited diffusion, so internalized Mav likely regulates growth throughout the arbor. In vertebrates, internalized Ret-GDNF complexes mediate long-range retrograde signaling from the periphery together with GFRα1-3 (Harrington and Ginty, 2013;Tuttle et al, 2019), but short-range signaling events have been less extensively characterized. Drosophila Ret contains a single isoform, so this system presents an opportunity to parse local and long-range Ret signaling functions without the additional complexity of Ret isoforms with different intracellular domains and trafficking properties (Tsui and Pierchala, 2010;Tuttle et al, 2019).…”