TheDrosophila Retgene functions in the stomatogastric nervous system with the Maverick TGFβ ligand and theGfrlco-receptor

Abstract

The RET receptor tyrosine kinase is crucial for the development of the enteric nervous system (ENS), acting as a receptor for Glial cell line-derived neurotrophic factor (GDNF) via GFR co-receptors. has a well-conserved RET homolog () that has been proposed to function independently of the co-receptor (). We find that is required for development of the stomatogastric (enteric) nervous system in both embryos and larvae, and its loss results in feeding defects. Live imaging analysis suggests that peristaltic waves are initiated but not propagated in mutant midguts. Examination of axons innervating the midgut reveals increased branching but the area covered by the branches is decreased. This phenotype can be rescued by expression. Additionally, shares the same ENS and feeding defects, suggesting that Ret and Gfrl might function together via a common ligand. We identified the TGFβ family member Maverick (Mav) as a ligand for Gfrl and a chromosomal deficiency displayed similar embryonic ENS defects. Our results suggest that the Ret and Gfrl families co-evolved before the separation of invertebrate and vertebrate lineages.

TGF-β Prodomain Alignments Reveal Unexpected Cysteine Conservation Consistent with Phylogenetic Predictions of Cross-Subfamily Heterodimerization

“…This is appropriate because GDNF shares pattern of cysteines with TGF-b family ligands yet signals strictly via a distinctive ternary complex with Ret tyrosine kinase receptors (e.g., Jing et al 1996). In contrast, Maverick primarily signals through TGF-b receptors but can also bind Ret (Myers et al 2018). This clear distinction in affinity supports our interpretation of data for Maverick.…”

Anatomy and Physiology of the Digestive Tract of Drosophila melanogaster

“…The adult digestive tract receives innervation from three distinct sources: the stomatogastric nervous system ( Hartenstein et al 1994 ; Gonzalez-Gaitan and Jackle 1995 ; Pankratz and Hoch 1995 ; Spiess et al 2008 ); the corpora cardiaca , neurosecretory structures which, in adult flies, are fused with one of the stomatogastric ganglia (the hypocerebral ganglion) ( Lee and Park 2004 ); and neurons located in the central nervous system (CNS), which extend their axons toward three different portions of the digestive tract ( Miguel-Aliaga and Thor 2004 ; Miguel-Aliaga et al 2008 ; Cognigni et al 2011 ; Talsma et al 2012 ; Schoofs et al 2014b ) ( Figure 5, A and B ). The Ret receptor tyrosine kinase, crucial for the development of the mammalian enteric nervous system, has recently been shown to contribute to the development of stomatogastric ganglia in flies ( Myers et al 2018 ). Ret remains expressed in most, if not all, gut-innervating neurons in adults, including stomatogastric as well as CNS neurons ( Perea et al 2017 ).…”

Ret and Substrate-Derived TGF-β Maverick Regulate Space-Filling Dendrite Growth in Drosophila Sensory Neurons

“…Intriguingly, the GFRAL/ GDF-15 complex signals through Ret in the mammalian brain stem to mediate GDF-15-dependent anti-obesity effects (Emmerson et al, 2017; Hsu et al, 2017; Mullican et al, 2017; Yang et al, 2017). In Drosophila , Ret , mav , and the GFR-like co-receptor form a biochemical complex and function in stomatogastric nervous system development (Myers et al, 2018). Thus, it seems plausible that Mav and Ret form a functional signaling pair here too, although neither GFRL nor classical TGF-β receptors play a role in space-filling dendrite growth of C4da neurons.…”