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The Journal of Neuroscience, September 30, 2009, 29(39):12174-12182; doi:10.1523/JNEUROSCI.2014-09.2009

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Development/Plasticity/Repair
Silencing the SPCA1 (Secretory Pathway Ca²⁺-ATPase Isoform 1) Impairs Ca²⁺ Homeostasis in the Golgi and Disturbs Neural Polarity

M. Rosario Sepúlveda,^1,2 Jo Vanoevelen,¹ Luc Raeymaekers,¹ Ana M. Mata,² and Frank Wuytack¹

¹Laboratory of Ca²⁺-transport ATPases, Department of Molecular Cell Biology, Faculty of Medicine, Catholic University of Leuven, B-3000 Leuven, Belgium, and ²Departamento de Bioquímica y Biología Molecular y Genética, Facultad de Ciencias, Universidad de Extremadura, 06071 Badajoz, Spain

Correspondence should be addressed to Dr. Frank Wuytack, Laboratory of Ca²⁺-transport ATPases, Department of Molecular Cell Biology, Faculty of Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. Email: Frank.Wuytack{at}med.kuleuven.be

Neural cell differentiation involves a complex regulatory signal transduction network in which Ca²⁺ ions and the secretory pathway play pivotal roles. The secretory pathway Ca²⁺-ATPase isoform 1 (SPCA1) is found in the Golgi apparatus where it is actively involved in the transport of Ca²⁺ or Mn²⁺ from the cytosol to the Golgi lumen. Its expression during brain development in different types of neurons has been documented recently, which raises the possibility that SPCA1 contributes to neuronal differentiation. In the present study, we investigated the potential impact of SPCA1 on neuronal polarization both in a cell line and in primary neuronal culture. In N2a neuroblastoma cells, SPCA1 was immunocytochemically localized in the juxtanuclear Golgi. Knockdown of SPCA1 by RNA interference markedly delayed the differentiation in these cells. The cells retarded in differentiation showed increased numbers of neurites of reduced length compared with control cells. Ca²⁺ imaging assays showed that the lack of SPCA1 impaired Golgi Ca²⁺ homeostasis and resulted in disturbed trafficking of different classes of proteins including normally Golgi-localized cameleon GT-YC3.3, bearing a Golgi-specific galactosyltransferase N terminus, and a normally plasma membrane-targeted, glycosyl phosphatidyl inositol-anchored cyan fluorescent protein construct. Also in hippocampal primary neurons, which showed a differential distribution of SPCA1 expression in Golgi stacks depending on differentiation stage, partial silencing of SPCA1 resulted in delayed differentiation, whereas total suppression drastically affected the cell survival. The disturbed overall cellular Ca²⁺ homeostasis and/or the altered targeting of organellar proteins under conditions of SPCA1 knockdown highlight the importance of SPCA1 function for normal neural differentiation.

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Received April 29, 2009; accepted Aug. 1, 2009.

Correspondence should be addressed to Dr. Frank Wuytack, Laboratory of Ca²⁺-transport ATPases, Department of Molecular Cell Biology, Faculty of Medicine, Katholieke Universiteit Leuven, B-3000 Leuven, Belgium. Email: Frank.Wuytack{at}med.kuleuven.be

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