Expression of the SMN Gene, the Spinal Muscular Atrophy Determining Gene, in the Mammalian Central Nervous System

Abstract

The survival motor neuron (SMN) gene is the putative disease gene for human spinal muscular atrophy (SMA), an autosomal recessive disorder characterized by progressive degeneration of lower motor neurons. Two copies of the gene, centromeric and telomeric, are present in the same 5q13 chromosomal region in humans. However, only the telomeric gene is affected in SMA. The SMN gene(s) encode(s) a novel protein of unknown function. To gain insights into the role of SMN in neurons, we have identified the SMN gene ortholog in the rat, and investigated SMN expression in the CNS of rat, monkey and humans by immunocytochemistry and in situ hybridization experiments. Antibodies against the SMN amino-terminus specifically recognized a single protein identical to the in vitro translation products of human and rat SMN cDNAs. The SMN gene transcript and product were widely but unevenly expressed throughout cerebral and spinal cord areas. The SMN protein was localized mainly in the cytoplasm of specific neuronal systems, and it was particularly expressed in lower motor neurons of newborn and adult animals. Likewise, a strong hybridization signal was detected in lamina IX of the spinal ventral horn. These results support the relevance of SMN for the motor neuron function and the pathogenetic role of the SMN gene in the neuronal degeneration associated with SMA.

An in vivo reporter system for measuring increased inclusion of exon 7 in SMN2 mRNA: potential therapy of SMA

“…3 Other species including mouse and rat only have the homologue of the telomeric copy of SMN. 4,5 The two SMN genes and their predicted proteins are identical except for a few translationally silent nucleotides within exon and intron sequences. The SMN1 copy is deleted or gene converted in more than 95% of SMA patients, 3,6 while mutations in SMN2 have no clinical consequence.…”

SMN protein analysis in fibroblast, amniocyte and CVS cultures from spinal muscular atrophy patients and its relevance for diagnosis

“…6 However, the two genes generate different proportions of alternatively spliced isoforms: about 90% of transcripts from the SMNt gene are full length, whilst the SMNc gene produces predominantly transcripts which lack exon 7 and, to a less amount, transcripts that lack exon 5 or both exons 5 and 7 as well as full length transcripts. 6,18 Both SMNt and SMNc are expressed in most if not all tissues; 6,[19][20][21] (own unpublished data 1996). Immunocytochemical studies of HeLa cells using monoclonal antibodies against SMN have shown that the protein is localised in both the cytoplasm and in the nucleus.…”

Solving the puzzle of spinal muscular atrophy: What are the missing pieces?

“…So far, we know that SMN is ubiquitous, conserved across species, highly expressed during early development, and that SMN levels are higher in spinal cord and brain, but significantly down-regulated after birth [Battaglia et al, 1997; La Bella et al, 1998;Williams et al, 1999]. The SMN protein is one member of a large, highly stable macromolecular complex that localizes in both the nuclear and cytoplasmic compartments of a cell [Liu and Dreyfuss, 1996].…”

“…The SMN protein is subject to both temporal and spatial regulation: the highest SMN levels have been reported in brain, spinal cord, kidney and heart [Lefebvre et al, 1997;Coovert et al, 1997;Burlet et al, 1998] and SMN is especially abundant throughout embryonic development [Battaglia et al, 1997;Burlet et al, 1998; La Bella et al, 1998]. The levels of SMN protein diminish during the early postnatal period; however, the timing of this repression varies among tissues [Kernochan et al, 2005].…”