The DAF-7/TGF-β signaling pathway regulates abundance of the Caenorhabditis elegans glutamate receptor GLR-1

Abstract

Transforming growth factor-β (TGF-β) family signaling pathways have roles in both neuronal development and the regulation of synaptic function. Here we identify a novel role for the C. elegans DAF-7/TGF-β signaling pathway in the regulation of the AMPA-type glutamate receptor GLR-1. We found that the abundance of GLR-1 increases at synapses in the ventral nerve cord (VNC) of animals with loss-of-function mutations in multiple DAF-7/TGF-β pathway components including the TGF-β ligand DAF-7, the type I receptor DAF-1, and the Smads DAF-8 and DAF-14. The GLR-1 defect can be rescued by expression of daf-8 specifically in glr-1-expressing interneurons. The effect on GLR-1 was specific for the DAF-7 pathway because mutations in the DBL-1/TGF-β family pathway did not increase GLR-1 levels in the VNC. Immunoblot analysis indicates that total levels of GLR-1 protein are increased in neurons of DAF-7/TGF-β pathway mutants. The increased abundance of GLR-1 in the VNC of daf-7 pathway mutants is dependent on the transcriptional regulator DAF-3/Smad suggesting that DAF-3-dependent transcription controls GLR-1 levels. Furthermore, we found that glr-1 transcription is increased in daf-7 mutants based on a glr-1 transcriptional reporter. Together these results suggest that the DAF-7/TGF-β signaling pathway functions in neurons and negatively regulates the abundance of GLR-1, in part, by controlling transcription of the receptor itself. Finally, DAF-7/TGF-β pathway mutants exhibit changes in spontaneous locomotion that are dependent on endogenous GLR-1 and consistent with increased glutamatergic signaling. These results reveal a novel mechanism by which TGF-β signaling functions in the nervous system to regulate behavior.

Developmental programming modulates olfactory behavior in C. elegans via endogenous RNAi pathways

“…A similar model of regulation by DAF-3 has been postulated for the myo-2 gene in the pharynx ( Thatcher et al, 1999 ). TGF-β signaling has also been shown to regulate neuronal receptor genes based on environmental cues via DAF-3-dependent and independent mechanisms in ASI, AWC, and interneurons ( Nolan et al, 2002 ; Lesch and Bargmann, 2010 ; McGehee et al, 2015 ). Since 977 genes in the genome contain the PD motif and the DAF-3 binding site is enriched in chemoreceptor genes ( McCarroll et al, 2005 ), we predict that DAF-3 might play a larger role in broadly establishing gene expression changes in response to environmental cues.…”

Inferring a spatial code of cell-cell interactions across a whole animal body

“…Netrin UNC-6 is an example ligand that serves as a cue for enabling DTC migration given its spatial pattern of expression 84 . Moreover, TGFβ-related signaling pathways regulate body size and therefore location of cells, sometimes involving proteins selected by the GA, such as DAF-7, DBL-1, SMA-6, SMA-10, LON-2, SRP-7, F14B4.1 and UNC-129 [85][86][87] . Similarly, mediators associated with Wnt signaling are required for axon guidance 88 and mutants of some of their encoding genes, such as cam-1 (ROR homolog that sequesters Wnts), cwn-1, lin-44, cfz-2, lin-17, lin-18 and mig-1, have previously been linked to defects of cell migration, positioning and patterning 50,[89][90][91] .…”

Transcriptomic Profiling of DAF-7/TGFβ Pathway Mutants in C. elegans

“…However, few studies have looked at the mechanisms by which the canonical pathway achieves these functions. DAF-7 has been demonstrated to affect the expression of olfactory chemoreceptors on chemosensory neurons, such as the ASI, and glutamate receptor GLR-1 in the ventral nerve cord [22,23]. It has also been shown to respond to pathogenic bacteria, Pseudomonas aeruginosa, in addition to other cues such as food, temperature, and pheromones [19,21].…”

“…This relationship has been observed in many other functions of the pathway, some of which may be conserved in higher animals, including humans. In addition to dauer formation, DAF-7 in C. elegans has been shown to play a role in regulating the expression of AMPA-type glutamate receptor GLR-1 [22], the expression of chemoreceptors in amphid neurons [23], the expression of genes in the distal tip cell to modulate the germline stem cell niche [24,25], and the production of prostaglandins that are important for sperm guidance [26]. In addition to dauer formation, DAF-7 in C. elegans has been shown to play a role in regulating the expression of AMPA-type glutamate receptor GLR-1 [22], the expression of chemoreceptors in amphid neurons [23], the expression of genes in the distal tip cell to modulate the germline stem cell niche [24,25], and the production of prostaglandins that are important for sperm guidance [26].…”