A multi-protein receptor-ligand complex underlies combinatorial dendrite guidance choices in C. elegans

Abstract

Ligand receptor interactions instruct axon guidance during development. How dendrites are guided to specific targets is less understood. The C. elegans PVD sensory neuron innervates muscle-skin interface with its elaborate dendritic branches. Here, we found that LECT-2, the ortholog of leukocyte cell-derived chemotaxin-2 (LECT2), is secreted from the muscles and required for muscle innervation by PVD. Mosaic analyses showed that LECT-2 acted locally to guide the growth of terminal branches. Ectopic expression of LECT-2 from seam cells is sufficient to redirect the PVD dendrites onto seam cells. LECT-2 functions in a multi-protein receptor-ligand complex that also contains two transmembrane ligands on the skin, SAX-7/L1CAM and MNR-1, and the neuronal transmembrane receptor DMA-1. LECT-2 greatly enhances the binding between SAX-7, MNR-1 and DMA-1. The activation of DMA-1 strictly requires all three ligands, which establishes a combinatorial code to precisely target and pattern dendritic arbors.DOI: http://dx.doi.org/10.7554/eLife.18345.001

A Dendritic Guidance Receptor Complex Brings Together Distinct Actin Regulators to Drive Efficient F-Actin Assembly and Branching

“…As a receptor for extrinsic dendritic branching signals, DMA-1 forms an inter-cellular complex by simultaneously binding to two membrane proteins on epidermis cells, SAX-7 and MNR-1, and the chemotactic molecule LECT-2 secreted from muscle cells (Diaz-Balzac et al, 2016; Dong et al, 2013; Salzberg et al, 2013; Zou et al, 2016). DMA-1 is a single-transmembrane protein.…”

“…SAX-7 forms a striped pattern on epidermis that correlates with the location of the 3 o and 4 o branches (Dong et al, 2013; Liang et al, 2015; Salzberg et al, 2013), whereas the epidermis-specific expression of MNR-1 specifies the attachment points for PVD dendrites (Dong et al, 2013; Salzberg et al, 2013). Both genetic and biochemical experiments support a model where the three ligand proteins from the epidermis/muscle cells, including SAX-7, MNR-1 and LECT-2, simultaneously bind to the extracellular domain of the dendrite-specific receptor DMA-1, leading to the formation of an inter-cellular complex which specifies the precise location of dendritic arborization (Diaz-Balzac et al, 2016; Liu and Shen, 2012; Zou et al, 2016). However, it remains unknown how this extrinsic cue is transmitted through DMA-1 to instruct intracellular signaling in the PVD neuron and, subsequently, drive dendrite branching.…”

“…The 3 o branches grow precisely along the border of the outer body wall muscles, while the 4 o branches innervate the narrow space between the epidermis and the body wall muscles, suggesting that the epidermal and muscle tissues provide guidance cues to regulate branch formation (Albeg et al, 2011). Indeed, a multi-protein ligand-receptor complex has been identified as an extrinsic cue in guiding PVD dendrite morphogenesis (Diaz-Balzac et al, 2016; Dong et al, 2013; Salzberg et al, 2013; Zou et al, 2016). This complex consists of the cell adhesion molecules SAX-7/L1CAM and MNR-1/Menorin, which are enriched in epidermis, the chemotaxin LECT-2/LECT2, which is secreted by the body wall muscle cells, and the cell adhesion receptor DMA-1, which is specifically expressed in PVD dendrites.…”

Separate transcriptionally regulated pathways specify distinct classes of sister dendrites in a nociceptive neuron

“…The LRR (Leucine Rich Repeat) protein DMA-1 likely acts in the same pathway as it shows a similar mutant PVD branching defect (Dong et al, 2013; Smith et al, 2013). DMA-1 mediates dendritic outgrowth as a PVD-expressed component of a quarternary complex containing the cell surface proteins SAX-7/L1CAM and Menorin/MNR-1 in the epidermis and the soluble factor LECT-2 (Díaz-Balzac et al, 2016; Dong et al, 2013; Liang et al, 2015; O’Brien et al, 2016; Salzberg et al, 2013; Zou et al, 2016). These interactions are necessary for 3° and 4° branching, but additional epidermal cues are likely required for pioneer 2° branch outgrowth as the dma-1 mutant phenotype is more severe than that of either sax-7 , mnr-1 , or lect-2 .…”

Worms on the spectrum - C. elegans models in autism research

“…16 primary dendrite development and branching pattern of the proprioceptive neuron PVD, and to orchestrate the molecular interactions during patterning of somatosensory dendrites Diaz-Balzac et al, 2016;Liu et al, 2016;Salzberg et al, 2013;Salzberg et al, 2014;Zou et al, 2016). sax-7/lad-1 is regulated by unc-44/ankyrin to maintain neuronal and axonal positioning (Sasakura et al, 2005;Zhou et al, 2008).…”