This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Khalili, K.
Right arrow Articles by Gordon, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Khalili, K.
Right arrow Articles by Gordon, J.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, October 2003, p. 6857-6875, Vol. 23, No. 19
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.19.6857-6875.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Pur{alpha} Is Essential for Postnatal Brain Development and Developmentally Coupled Cellular Proliferation As Revealed by Genetic Inactivation in the Mouse

Kamel Khalili,1* Luis Del Valle,1 Vandhana Muralidharan,1 William J. Gault,1 Nune Darbinian,1 Jessica Otte,1 Ellen Meier,1 Edward M. Johnson,2 Dianne C. Daniel,2 Yayoi Kinoshita,2 Shohreh Amini,1 and Jennifer Gordon1

Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, Philadelphia, Pennsylvania 19122,1 Departments of Pathology and Molecular Biology and The D. H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 100292

Received 23 July 2002/ Returned for modification 12 September 2002/ Accepted 10 April 2003

The single-stranded DNA- and RNA-binding protein, Pur{alpha}, has been implicated in many biological processes, including control of transcription of multiple genes, initiation of DNA replication, and RNA transport and translation. Deletions of the PURA gene are frequent in acute myeloid leukemia. Mice with targeted disruption of the PURA gene in both alleles appear normal at birth, but at 2 weeks of age, they develop neurological problems manifest by severe tremor and spontaneous seizures and they die by 4 weeks. There are severely lower numbers of neurons in regions of the hippocampus and cerebellum of PURA-/- mice versus those of age-matched +/+ littermates, and lamination of these regions is aberrant at time of death. Immunohistochemical analysis of MCM7, a protein marker for DNA replication, reveals a lack of proliferation of precursor cells in these regions in the PURA-/- mice. Levels of proliferation were also absent or low in several other tissues of the PURA-/- mice, including those of myeloid lineage, whereas those of PURA+/- mice were intermediate. Evaluation of brain sections indicates a reduction in myelin and glial fibrillary acidic protein labeling in oligodendrocytes and astrocytes, respectively, indicating pathological development of these cells. At postnatal day 5, a critical time for cerebellar development, Pur{alpha} and Cdk5 were both at peak levels in bodies and dendrites of Purkinje cells of PURA+/+ mice, but both were absent in dendrites of PURA-/- mice. Pur{alpha} and Cdk5 can be coimmunoprecipitated from brain lysates of PURA+/+ mice. Immunohistochemical studies reveal a dramatic reduction in the level of both phosphorylated and nonphosphorylated neurofilaments in dendrites of the Purkinje cell layer and of synapse formation in the hippocampus. Overall results are consistent with a role for Pur{alpha} in developmentally timed DNA replication in specific cell types and also point to a newly emerging role in compartmentalized RNA transport and translation in neuronal dendrites.

* Corresponding author. Mailing address: Center for Neurovirology and Cancer Biology, College of Science and Technology, Temple University, 1900 North 12th St., 015-96, Room 203, Philadelphia, PA 19122. Phone: (215) 204-0678. Fax: (215) 204-0679. E-mail: kamel.khalili{at}temple.edu.

Molecular and Cellular Biology, October 2003, p. 6857-6875, Vol. 23, No. 19
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.19.6857-6875.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Huang, C. C., Chiribau, C.-B., Majumder, M., Chiang, C.-M., Wek, R. C., Kelm, R. J. Jr., Khalili, K., Snider, M. D., Hatzoglou, M. (2009). A Bifunctional Intronic Element Regulates the Expression of the Arginine/Lysine Transporter Cat-1 via Mechanisms Involving the Purine-rich Element Binding Protein A (Pur{alpha}). J. Biol. Chem. 284: 32312-32320 [Abstract] [Full Text]  
  • Graebsch, A., Roche, S., Niessing, D. (2009). X-ray structure of Pur-{alpha} reveals a Whirly-like fold and an unusual nucleic-acid binding surface. Proc. Natl. Acad. Sci. USA 106: 18521-18526 [Abstract] [Full Text]  
  • Hashem, V., Galloway, J. N., Mori, M., Willemsen, R., Oostra, B. A., Paylor, R., Nelson, D. L. (2009). Ectopic expression of CGG containing mRNA is neurotoxic in mammals. Hum Mol Genet 18: 2443-2451 [Abstract] [Full Text]  
  • O'Rourke, J. R., Swanson, M. S. (2009). Mechanisms of RNA-mediated Disease. J. Biol. Chem. 284: 7419-7423 [Abstract] [Full Text]  
  • Kobayashi, Y., Suzuki, K., Kobayashi, H., Ohashi, S., Koike, K., Macchi, P., Kiebler, M., Anzai, K. (2008). C9orf10 Protein, a Novel Protein Component of Pur{alpha}-containing mRNA-protein Particles (Pur{alpha}-mRNPs): Characterization of Developmental and Regional Expressions in the Mouse Brain. J. Histochem. Cytochem. 56: 723-731 [Abstract] [Full Text]  
  • Ranpura, S. A., Deshmukh, U., Reddi, P. P. (2008). NF45 and NF90 in Murine Seminiferous Epithelium: Potential Role in SP-10 Gene Transcription. J Androl 29: 186-197 [Abstract] [Full Text]  
  • Zhang, A., David, J. J., Subramanian, S. V., Liu, X., Fuerst, M. D., Zhao, X., Leier, C. V., Orosz, C. G., Kelm, R. J. Jr., Strauch, A. R. (2008). Serum response factor neutralizes Pur{alpha}- and Pur{beta}-mediated repression of the fetal vascular smooth muscle {alpha}-actin gene in stressed adult cardiomyocytes. Am. J. Physiol. Cell Physiol. 294: C702-C714 [Abstract] [Full Text]  
  • Knapp, A. M., Ramsey, J. E., Wang, S.-X., Strauch, A. R., Kelm, R. J. Jr. (2007). Structure-Function Analysis of Mouse Pur II: CONFORMATION ALTERING MUTATIONS DISRUPT SINGLE-STRANDED DNA AND PROTEIN INTERACTIONS CRUCIAL TO SMOOTH MUSCLE {alpha}-ACTIN GENE REPRESSION. J. Biol. Chem. 282: 35899-35909 [Abstract] [Full Text]  
  • Ji, J., Tsika, G. L., Rindt, H., Schreiber, K. L., McCarthy, J. J., Kelm, R. J. Jr., Tsika, R. (2007). Pur{alpha} and Pur{beta} Collaborate with Sp3 To Negatively Regulate {beta}-Myosin Heavy Chain Gene Expression during Skeletal Muscle Inactivity. Mol. Cell. Biol. 27: 1531-1543 [Abstract] [Full Text]  
  • Ramsey, J. E., Daugherty, M. A., Kelm, R. J. Jr. (2007). Hydrodynamic Studies on the Quaternary Structure of Recombinant Mouse Purbeta. J. Biol. Chem. 282: 1552-1560 [Abstract] [Full Text]  
  • Knapp, A. M., Ramsey, J. E., Wang, S.-X., Godburn, K. E., Strauch, A. R., Kelm, R. J. Jr. (2006). Nucleoprotein Interactions Governing Cell Type-dependent Repression of the Mouse Smooth Muscle {alpha}-Actin Promoter by Single-stranded DNA-binding Proteins Pur{alpha} and Purbeta. J. Biol. Chem. 281: 7907-7918 [Abstract] [Full Text]  
  • Kinoshita, Y., Johnson, E. M. (2004). Site-specific Loading of an MCM Protein Complex in a DNA Replication Initiation Zone Upstream of the c-MYC Gene in the HeLa Cell Cycle. J. Biol. Chem. 279: 35879-35889 [Abstract] [Full Text]  
  • Limesand, S. W., Jeckel, K. M., Anthony, R. V. (2004). Pur{alpha}, a Single-Stranded Deoxyribonucleic Acid Binding Protein, Augments Placental Lactogen Gene Transcription. Mol. Endocrinol. 18: 447-457 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»