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Human Molecular Genetics Advance Access originally published online on October 19, 2005
Human Molecular Genetics 2005 14(23):3629-3642; doi:10.1093/hmg/ddi390
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© The Author 2005. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

The activity of the spinal muscular atrophy protein is regulated during development and cellular differentiation

Francesca Gabanella1, Claudia Carissimi1, Alessandro Usiello2,3 and Livio Pellizzoni1,*

1Dulbecco Telethon Institute, Institute of Cell Biology (CNR), I-00016 Monterotondo Scalo, Rome, Italy, 2Department of Neuroscience, Karolinska Institutet, S-17177 Stockholm, Sweden and 3CEINGE Biotecnologie Avanzate, I-80145 Napoli, Italy

* To whom correspondence should be addressed. Tel: +39 0690091326; Fax: +39 0690091259; Email: livio.pellizzoni{at}ibc.cnr.it

Received September 14, 2005; Accepted October 12, 2005

Spinal muscular atrophy (SMA) is a lethal neuromuscular disease caused by reduced levels of expression of the survival motor neuron (SMN) protein. SMN is part of a macromolecular complex essential for the assembly of the small nuclear ribonucleoproteins (snRNPs) that carry out pre-mRNA splicing. Although the SMN complex has the potential to control the pathway of snRNP biogenesis, it is not known whether SMN function in snRNP assembly is regulated. Here, we analyze SMN interactions and function in mouse tissues and show that, when normalized per cell number, similar levels of the SMN complex are expressed throughout the ontogenesis of the central nervous system (CNS). Strikingly, however, SMN function in snRNP assembly in extracts does not correlate with its expression levels and it varies greatly both among tissues and during development. The highest levels of SMN activity are found during the embryonic and early postnatal development of the CNS and are followed by a sharp decrease to a basal level, which is then maintained throughout life. This downregulation takes place in the spinal cord earlier than in the brain and coincides with the onset of myelination. Using model cell systems and pulse-labeling experiments, we further show that SMN activity and snRNP synthesis are strongly downregulated upon neuronal as well as myogenic differentiation, and linked to the rate of global transcription of postmitotic neurons and myotubes. These results demonstrate that the SMN complex activity in snRNP assembly is regulated and point to a differential requirement for SMN function during development and cellular differentiation.


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