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Human Molecular Genetics Advance Access published online on October 19, 2005
Human Molecular Genetics, doi:10.1093/hmg/ddi390
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© The Author 2005. Published by Oxford University Press. All rights reserved
Received September 14, 2005
Revised October 12, 2005
Accepted October 12, 2005

Article

The activity of the Spinal Muscular Atrophy protein is regulated during development and cellular differentiation

Francesca Gabanella 1, Claudia Carissimi 1, Alessandro Usiello 2, and Livio Pellizzoni 1*

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

* To whom correspondence should be addressed.
Livio Pellizzoni, E-mail: livio.pellizzoni{at}ibc.cnr.it


  Abstract

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 down regulation 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 down regulated 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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