Abstract
NCLX is a Na+/Ca2+ exchanger that uses energy stored in the transmembrane sodium gradient to facilitate the exchange of sodium ions for ionic calcium. Mammals have a single NCLX, which has been shown to function primarily at the mitochondrion and is an important regulator of neuronal physiology by contributing to neurotransmission and synaptic plasticity. The role of NCLX in developmental cell patterning (e.g. in neural circuits) is largely unknown. Here we describe a novel role for the Caenorhabditis elegans NCLX-type protein, NCX-9, in neural circuit formation. NCX-9 functions in hypodermal seam cells that secrete the axon guidance cue UNC-129/BMP, and our data revealed that ncx-9-/- mutant animals exhibit development defects in stereotyped left/right axon guidance choices within the GABAergic motor neuron circuit. Our data also implicate NCX-9 in a LON-2/heparan sulfate and UNC-6/netrin-mediated, RAC-dependent signaling pathway to guide left/right patterning within this circuit. Finally, we also provide in vitro physiology data supporting the role for NCX-9 in handling calcium exchange at the mitochondrion. Taken together, our work reveals the specificity by which the handling by NCLX of calcium exchange can map to neural circuit patterning and axon guidance decisions during development.
Highlights
NCLX is a Na؉/Ca2؉ exchanger that uses energy stored in the transmembrane sodium gradient to facilitate the exchange of sodium ions for ionic calcium
The focus of our research described here is on the NCLX-type exchanger, Naϩ/Ca2ϩ exchangers (NCX)-9, in Caenorhabditis elegans, for which we identify a role in the development of D-type motor neurons that form a GABAergic commissural motor neuron circuit
We find that NCX-9 functions developmentally to organize neural circuit architecture
Summary
Ncx-9(gk234237);max-2(cy2) double mutants show a mild but significant enhancement in the average number of VD/DD commissures per animal that fail to reach the dorsal nerve cord when compared with wild type or the single mutants of ncx-9(gk234237) and max-2(cy2) (Fig. 3D; *, p Ͻ 0.005 versus wild type; n ϭ 50 for all strains examined) This indicates that NCX-9 may have a role in commissural guidance of VD/DD motor neurons. We observed significant enhancement of commissural guidance defects in hst-6(ok273);unc40(n324) double mutants when compared with wild type or single mutants of hst-6(ok273) and unc-40(n324) (Fig. 4F; *, p Ͻ 0.005 versus wild type; n ϭ 100 for all strains examined) These data show that NCX-9 functions in the same pathway as LON2/glypican and HS modifiers HST-2 and HST-6 and works parallel to SDN-1/syndecan to set left/right patterning of the VD/DD GABAergic circuit. These in vitro experiments demonstrate that NCX-9, like NCLX [5], is localized at the mitochondria and regulates sodium calcium exchange in these organelles
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