The NCLX-type Na/Ca Exchanger NCX-9 Is Required for Patterning of Neural Circuits in

Overview

Journal J Biol Chem

Specialty Biochemistry

Date 2017 Feb 16

PMID 28196860

Citations 11

Authors

Vishal Sharma

Soumitra Roy

Israel Sekler

Damien M OHalloran

Affiliations

Soon will be listed here.

Abstract

NCLX is a Na/Ca 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 ( in neural circuits) is largely unknown. Here we describe a novel role for the 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 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 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.

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References

Rhiner C, Gysi S, Frohli E, Hengartner M, Hajnal A . Syndecan regulates cell migration and axon guidance in C. elegans. Development. 2005; 132(20):4621-33. DOI: 10.1242/dev.02042. View

Hedgecock E, Culotti J, Hall D . The unc-5, unc-6, and unc-40 genes guide circumferential migrations of pioneer axons and mesodermal cells on the epidermis in C. elegans. Neuron. 1990; 4(1):61-85. DOI: 10.1016/0896-6273(90)90444-k. View

Dejima K, Seko A, Yamashita K, Gengyo-Ando K, Mitani S, Izumikawa T . Essential roles of 3'-phosphoadenosine 5'-phosphosulfate synthase in embryonic and larval development of the nematode Caenorhabditis elegans. J Biol Chem. 2006; 281(16):11431-40. DOI: 10.1074/jbc.M601509200. View

Wadsworth W, Bhatt H, Hedgecock E . Neuroglia and pioneer neurons express UNC-6 to provide global and local netrin cues for guiding migrations in C. elegans. Neuron. 1996; 16(1):35-46. DOI: 10.1016/s0896-6273(00)80021-5. View

Hutter H, Wacker I, Schmid C, Hedgecock E . Novel genes controlling ventral cord asymmetry and navigation of pioneer axons in C. elegans. Dev Biol. 2005; 284(1):260-72. DOI: 10.1016/j.ydbio.2005.05.025. View

Li Z, Matsuoka S, Hryshko L, Nicoll D, Bersohn M, Burke E . Cloning of the NCX2 isoform of the plasma membrane Na(+)-Ca2+ exchanger. J Biol Chem. 1994; 269(26):17434-9. View

Brenner S . The genetics of Caenorhabditis elegans. Genetics. 1974; 77(1):71-94. PMC: 1213120. DOI: 10.1093/genetics/77.1.71. View

Sharma V, He C, Sacca-Schaeffer J, Brzozowski E, Martin-Herranz D, Mendelowitz Z . Insight into the family of Na+/Ca2+ exchangers of Caenorhabditis elegans. Genetics. 2013; 195(2):611-9. PMC: 3781985. DOI: 10.1534/genetics.113.153106. View

Gysi S, Rhiner C, Flibotte S, Moerman D, Hengartner M . A network of HSPG core proteins and HS modifying enzymes regulates netrin-dependent guidance of D-type motor neurons in Caenorhabditis elegans. PLoS One. 2013; 8(9):e74908. PMC: 3774775. DOI: 10.1371/journal.pone.0074908. View

10.

Palty R, Silverman W, Hershfinkel M, Caporale T, Sensi S, Parnis J . NCLX is an essential component of mitochondrial Na+/Ca2+ exchange. Proc Natl Acad Sci U S A. 2009; 107(1):436-41. PMC: 2806722. DOI: 10.1073/pnas.0908099107. View

11.

White J, Southgate E, Thomson J, Brenner S . The structure of the nervous system of the nematode Caenorhabditis elegans. Philos Trans R Soc Lond B Biol Sci. 2012; 314(1165):1-340. DOI: 10.1098/rstb.1986.0056. View

12.

Blanchette C, Thackeray A, Perrat P, Hekimi S, Benard C . Functional Requirements for Heparan Sulfate Biosynthesis in Morphogenesis and Nervous System Development in C. elegans. PLoS Genet. 2017; 13(1):e1006525. PMC: 5221758. DOI: 10.1371/journal.pgen.1006525. View

13.

Sheng J, Prinsen C, Clark R, Giles W, Schnetkamp P . Na(+)-Ca(2+)-K(+) currents measured in insect cells transfected with the retinal cone or rod Na(+)-Ca(2+)-K(+) exchanger cDNA. Biophys J. 2000; 79(4):1945-53. PMC: 1301085. DOI: 10.1016/S0006-3495(00)76443-5. View

14.

Bulow H, Tjoe N, Townley R, Didiano D, van Kuppevelt T, Hobert O . Extracellular sugar modifications provide instructive and cell-specific information for axon-guidance choices. Curr Biol. 2008; 18(24):1978-85. PMC: 2765105. DOI: 10.1016/j.cub.2008.11.023. View

15.

Boulin T, Etchberger J, Hobert O . Reporter gene fusions. WormBook. 2007; :1-23. PMC: 4781452. DOI: 10.1895/wormbook.1.106.1. View

16.

Norris A, Sundararajan L, Morgan D, Roberts Z, Lundquist E . The UNC-6/Netrin receptors UNC-40/DCC and UNC-5 inhibit growth cone filopodial protrusion via UNC-73/Trio, Rac-like GTPases and UNC-33/CRMP. Development. 2014; 141(22):4395-405. PMC: 4302909. DOI: 10.1242/dev.110437. View

17.

Gobbi P, Castaldo P, Minelli A, Salucci S, Magi S, Corcione E . Mitochondrial localization of Na+/Ca2+ exchangers NCX1-3 in neurons and astrocytes of adult rat brain in situ. Pharmacol Res. 2007; 56(6):556-65. DOI: 10.1016/j.phrs.2007.10.005. View

18.

Ding M, Woo W, Chisholm A . The cytoskeleton and epidermal morphogenesis in C. elegans. Exp Cell Res. 2004; 301(1):84-90. DOI: 10.1016/j.yexcr.2004.08.017. View

19.

Nita I, Hershfinkel M, Fishman D, Ozeri E, Rutter G, Sensi S . The mitochondrial Na+/Ca2+ exchanger upregulates glucose dependent Ca2+ signalling linked to insulin secretion. PLoS One. 2012; 7(10):e46649. PMC: 3466326. DOI: 10.1371/journal.pone.0046649. View

20.

Lucanic M, Kiley M, Ashcroft N, LEtoile N, Cheng H . The Caenorhabditis elegans P21-activated kinases are differentially required for UNC-6/netrin-mediated commissural motor axon guidance. Development. 2006; 133(22):4549-59. DOI: 10.1242/dev.02648. View