Precise regulation of the guidance receptor DMA-1 by KPC-1/Furin instructs dendritic branching decisions

Abstract

Extracellular adhesion molecules and their neuronal receptors guide the growth and branching of axons and dendrites. Growth cones are attracted to intermediate targets, but they must switch their response upon arrival so that they can move away and complete the next stage of growth. Here, we show that KPC-1, a C. elegans Furin homolog, regulates the level of the branching receptor DMA-1 on dendrites by targeting it to late endosomes. In kpc-1 mutants, the level of DMA-1 is abnormally high on dendrites, resulting in trapping of dendrites at locations where a high level of the cognate ligand, the adhesion molecule SAX-7/L1, is present. The misregulation of DMA-1 also causes dendritic self-avoidance defects. Thus, precise regulation of guidance receptors creates flexibility of responses to guidance signals and is critical for neuronal morphogenesis.

DOI: http://dx.doi.org/10.7554/eLife.11008.001

eLife digest

Neurons are the principal cells in the nervous system that send and receive information. A vast network of neurons helps transmit information throughout the brain and body. The end of the neuron that receives messages forms branched structures called dendrites, the shapes of which determine the signals the neuron receives. Therefore, establishing the correct shape of the dendrites is critical for the neurons to work correctly.

As dendrites grow during development, signals from the environment tell them where to branch and where to stop. For example, the neurons that transmit information about touch respond to signals from skin cells to guide the growth of their dendrites. These signals bind to receptor proteins on the surface of the neuron. However, the environment around the neurons also contains many guidance signals that the neurons must ignore.

Dong et al. now show that touch neurons control how they respond to signals by adjusting the abundance of the receptors on their surface. First, genetic mutations were identified that distort the shape of the dendrites of touch-sensing neurons in a simple worm called Caenorhabditis elegans. These neurons lacked the equivalent of an enzyme called Furin and had abnormally high amounts of a receptor protein called DMA-1 on their surfaces. This suggests that controlling the receptor level on dendrites creates flexibility in the guidance choices of dendrites.

Furin usually cuts up proteins. However, Dong et al. found that Furin prevents DMA-1 from inserting into the membrane of neurons by binding to the receptors and sending them to the lysosomes, cellular compartments where proteins are destroyed. Reducing the number of receptors at the surface of the cell in this way prevents the neuron from responding to the guidance signals at wrong locations. In the future, more studies are needed to understand how the neuron checks and balances this process and how it eventually is turned off.

DOI: http://dx.doi.org/10.7554/eLife.11008.002