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First published online 31 January 2006
doi: 10.1242/jcs.02782

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Distinct domains of the spinal muscular atrophy protein SMN are required for targeting to Cajal bodies in mammalian cells

¹ Laboratoire de Biologie Cellulaire des Membranes, Institut Jacques Monod (IJM), UMR 7592 CNRS/Universités Paris 6 et 7, 2 Place Jussieu, 75251 Paris Cedex 05, France
² Service de Cytométrie, IJM 75251 Cedex 05 Paris, France
³ Laboratoire de Morphométrie et Modélisation Cellulaire, IJM, 75251 Cedex 05 Paris, France
⁴ UR393 INSERM, IRNEM Institute, Hôpital Necker-Enfants Malades, Paris, France

^* Author for correspondence (e-mail: lefebvre{at}ijm.jussieu.fr)

Accepted 7 November 2005

Mutations of the survival motor neuron gene SMN1 cause the inherited disease spinal muscular atrophy (SMA). The ubiquitous SMN protein facilitates the biogenesis of spliceosomal small nuclear ribonucleoproteins (snRNPs). The protein is detected in the cytoplasm, nucleoplasm and enriched with snRNPs in nuclear Cajal bodies. It is structurally divided into at least an amino-terminal region rich in basic amino acid residues, a central Tudor domain, a self-association tyrosine-glycine-box and an exon7-encoded C-terminus. To examine the domains required for the intranuclear localization of SMN, we have used fluorescently tagged protein mutants transiently overexpressed in mammalian cells. The basic amino acid residues direct nucleolar localization of SMN mutants. The Tudor domain promotes localization of proteins in the nucleus and it cooperates with the basic amino acid residues and the tyrosine-glycine-box for protein localization in Cajal bodies. Moreover, the most frequent disease-linked mutant SMNex7 reduces accumulation of snRNPs in Cajal bodies, suggesting that the C-terminus of SMN participates in targeting to Cajal bodies. A reduced number of Cajal bodies in patient fibroblasts associates with the absence of snRNPs in Cajal bodies, revealing that intranuclear snRNA organization is modified in disease. These results indicate that direct and indirect mechanisms regulate localization of SMN in Cajal bodies.

Key words: Gems, Cajal bodies, Tudor domain, SMN, SnRNPs, SMA

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