Abstract
The cell nucleus contains two closely related structures, Cajal bodies (CBs) and gems. CBs are the first site of accumulation of newly assembled splicing snRNPs (small nuclear ribonucleoproteins) following their import into the nucleus, before they form their steady-state localization in nuclear splicing speckles. Gems are the nuclear site of accumulation of survival motor neurons (SMNs), an insufficiency of which leads to the inherited neurodegenerative condition, spinal muscular atrophy (SMA). SMN is required in the cytoplasm for the addition of core, Sm, proteins to new snRNPs and is believed to accompany snRNPs to the CB. In most cell lines, gems are indistinguishable from CBs, although the structures are often separate in vivo. The relationship between CBs and gems is not fully understood, but there is evidence that symmetrical dimethylation of arginine residues in the CB protein coilin brings them together in HeLa cells. During neuronal differentiation of the human neuroblastoma cell line SH-SY5Y, CBs and gems increase their colocalization, mimicking changes seen during foetal development. This does not result from alterations in the methylation of coilin, but from increased levels of SMN. Expression of exogenous SMN results in an increased efficiency of snRNP transport to nuclear speckles. This suggests different mechanisms are present in different cell types and in vivo that may be significant for the tissue-specific pathology of SMA.
Highlights
We have investigated the relationship between Cajal bodies (CBs) and gems and the methylation of endogenous coilin in the human neuroblastoma cell line SH-SY5Y as it undergoes differentiation and neurite outgrowth
CBs are identified by the presence of coilin and are implicated in nuclear stages of splicing small nuclear ribonucleoproteins (snRNPs) maturation, while gems contain the survival motor neurons (SMNs) protein known to be important for earlier, cytoplasmic, stages of snRNP biogenesis
The neuroblastoma cell line, SH-SY5Y, can be induced to undergo differentiation in vitro by addition of retinoic acid (RA) (Figure 1C,D) or by the sequential use of RA followed by brain-derived neurotrophic factor (BDNF) (Figure 1E,F) [30,31]
Summary
In vivo CBs and gems are often seen as separate structures in foetal tissues, with the percentage of nuclear bodies containing both SMN and coilin increasing with foetal age This suggests that their colocalization may be developmentally regulated [3]. It has been suggested that lowered levels of SMN selectively affect the www.traffic.dk 1585 biogenesis of certain snRNPs, those involved in the minor spliceosome [22,23] and lead to widespread splicing defects [23]. It is clear, that a fuller understanding of the mechanisms controlling snRNP biogenesis is required. As the prevailing view is that the role of the CB/gem complex is to increase the efficiency of snRNP maturation [11,28], these findings have important implications for the understanding of the tissue-specific nature of SMA
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