ZPR1 is essential for survival and is required for localization of the survival motor neurons (SMN) protein to Cajal bodies.
Mutation of the survival motor neurons 1 (SMN1) gene causes motor neuron apoptosis and represents the major cause of spinal muscular atrophy in humans. Biochemical studies have established that the SMN protein plays an important role in spliceosomal small nuclear ribonucleoprotein (snRNP) biogenesis and that the SMN complex can interact with the zinc finger protein ZPR1. Here we report that targeted ablation of the Zpr1 gene in mice disrupts the subcellular localization of both SMN and spliceosomal snRNPs. Specifically, SMN localization to Cajal bodies and gems was not observed in cells derived from Zpr1-/- embryos and the amount of cytoplasmic snRNP detected in Zpr1-/- embryos was reduced compared with that in wild-type embryos. We found that Zpr1-/- mice die during early embryonic development, with reduced proliferation and increased apoptosis. These effects of Zpr1 gene disruption were confirmed and extended in studies of cultured motor neuron-like cells using small interfering RNA-mediated Zpr1 gene suppression; ZPR1 deficiency caused growth cone retraction, axonal defects, and apoptosis. Together, these data indicate that ZPR1 contributes to the regulation of SMN complexes and that it is essential for cell survival.
Gangwani
Laxman
L
Program in Molecular Medicine, Howard Hughes Medical Institute, University of Massachusetts Medical School, 373 Plantation St., Worcester, MA 01605, USA.
Flavell
Richard A
RA
Davis
Roger J
RJ
D000818:Animals; D017209:Apoptosis; D001369:Axons / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D020541:Coiled Bodies / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein; D015870:Gene Expression; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008855:Microscopy, Electron, Scanning; D009046:Motor Neurons / Q000166:cytology* / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D021381:Protein Transport; D034622:RNA Interference; D016601:RNA-Binding Proteins; D020718:Ribonucleoproteins, Small Nucleolar / Q000378:metabolism; D055532:SMN Complex Proteins; D017381:Spliceosomes / Q000378:metabolism; D055533:Survival of Motor Neuron 1 Protein
D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D020718:Ribonucleoproteins, Small Nucleolar; D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526472:Smn1 protein, mouse; D055533:Survival of Motor Neuron 1 Protein; C490987:Zfp259 protein, mouse