The SMN Protein Function

The SMN proteins encoded by FL-SMN1 and FL-SMN2 transcripts are identical. Both genes are ubiquitously expressed. The SMN protein is present in the cytoplasm as well as in the nucleus, where it is localized in the so-called gemini of coiled bodies (gems) as well as in the coiled (Cajal) bodies (Lefebvre et al. 1995; Liu et al. 1997; Young et al. 2000). SMN is part of a multiprotein complex containing numerous SMN-interacting proteins (sometimes referred to as Gemin 2-7) and the Sm class of spliceo-somal U snRNPs (Liu and Dreyfuss 1996; Liu et al. 1997; Charroux et al. 1999; Charroux et al. 2000; Baccon et al. 2002; Gubitz et al. 2002; Meister et al. 2002; Pellizzoni et al. 2002). In addition the SMN complex has been shown to transiently interact with spliceosomal snRNPs U1, U2, U4, and U5 (Meister et al. 2002). The SMN protein has a major housekeeping function in the assembly and disassembly of the diverse small nuclear ribonucleoproteins (snRNP) and in pre-mRNA splicing (Fischer et al. 1997; Pellizzoni et al. 1998). Interestingly, functional studies indicated that the SMN complex mediates the formation of spliceosomal U snRNPs in an ATP-dependent manner and thus functions as an RNP chaperone (Liu et al. 1997; Meister et al. 2001). Although the molecular basis of this assisted RNP assembly is poorly understood so far, some important interactions of the SMN complex have been revealed by these studies.

Despite the vast knowledge concerning the SMN biochemistry, it remains unclear how an impaired ubiquitous SMN function in spliceoso-mal biogenesis specifically causes alpha motor neuron degeneration. This raises the question of whether SMN fulfills an additional function exclusively in alpha motor neurons. Immunocytochemical studies have localized SMN in dendrites and axons and suggest a role in transport of RNA along the axons (Bechade et al. 1999; Pagliardini et al. 2000). Zhang and colleagues showed that the SMN protein is localized in granules present in neurites and growth cones of cultured neuronal cells. SMN-containing granules exhibited rapid, bidirectional movements depending on both microtubules and microfilaments (Rossoll et al. 2003; Zhang et al. 2003).

SMN is highly expressed during embryogenesis, but levels decline rapidly after birth. In SMA-transgenic mice, the length of the dendrites is significantly reduced, whereas the number of motor neurons is not significantly affected as compared to controls (Monani et al. 2000). Conditional neuronal knock-out mice (SmnA7) lack axonal sprouting (Cifuentes-Diaz et al. 2002).

Consistent with these findings, knock-down of the Smn protein by antisense morpholinos in zebrafish embryos has revealed a significant axonal dysmorphology. These fail to reach motor neuron endplates due to early branching and truncation, which suggests an important role of SMN in the pathfinding of axons (McWhorter et al. 2003).

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