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The nucleus is separated from the cytoplasm by a double membrane. The outer nuclear membrane is continuous with the endoplasmic reticulum (Spector, 2001; Lamond and Sleeman, 2003). Exchange of proteins and miRNA between the cytoplasm and the nucleus occurs through multi-protein structures situated in the nuclear envelope known as nuclear pores. The nucleus is compartmentalized and contains numerous sub-nuclear bodies, including nucleoli, splicing speckles, Cajal bodies (CB), gems and promyelocytic leukemia (PML) bodies in addition to chromosomes. In contrast to cytoplasmic compartments, the sub-nuclear bodies lack a membrane separating them from the nucleoplasm. The build up of factors in these distinct sub-nuclear bodies may serve to enhance the efficiency of specific nuclear processes.
Fig 1. Nuclear domains
Chromosomes are organized into large domains called chromosome territories (Spector, 2001; Lamond and Sleeman, 2003). Chromosomes exhibit different levels of compaction with the most condensed regions referred to as heterochromatin, which is either lacking in genes or contains genes that are transcriptionally repressed. Less condensed regions of chromosomes are known as euchromatin, which is rich in gene concentration and is usually, but not always, actively transcribed.
Most mammalian cells contain 1-5 nucleoli each 0.5-5 µm in diameter (Spector, 2001; Lamond and Sleeman, 2003; Zimber et al., 2004; Handwerger and Gall, 2006). The nucleolus contains three distinguishable regions, the fibrillar centres (FCs), which are surrounded by the dense fibrillar component (DFC) and the granular component (GC) that constitutes the rest of the nucleolus. Nucleoli form around tendemly repeated clusters of ribosomal RNA (rRNA) genes. These loci are termed nucleolar organizer regions (NORs). The function of the nucleolus is to synthesize rRNA and assemble ribosomal subunits. The rRNA genes are transcribed by RNA polymerase I as a large pre-rRNA precursor that is cleaved to produce 5.8S, 18S, and 28S rRNAs found in ribosomes. rRNA is post-transcriptionally modified and assembled with ribosomal proteins, which are synthesized in the cytoplasm and imported into the nucleus through the nuclear pores. This results in the formation of the large and small ribosomal sub-units, which are subsequently transported from the nucleus to the cytoplasm where they mediate mRNA translation.
Speckles are irregular shaped structures of varied size and the nucleus typically contains 25-50 of these sub-nuclear bodies (Spector, 2001; Lamond and Sleeman, 2003). Nuclear speckles are rich in splicing factors including small nuclear ribonucleoprotein particles (snRNPs) and non-snRNP protein splicing factors such as splicing factor SC35. Speckles are often found close to actively transcribed genes and are thought to act as a reservoir for the splicing of nascent pre-mRNA at nearby genes.
Numerous Cajal bodies, or coiled bodies are found in many cell types and are typically 0.2-1 µm in diameter (Matera, 1999). These structures appear as a tangle of coiled threads and are characterized by the presence of the p80 coilin protein. Cajal bodies are thought to play a role in snRNP biogenesis and in the trafficking of snRNPs and small nucleolar RNPs (snoRNPs). Cajal bodies are rich in spliceosomal U1, U2, U4/U6 and U5 snRNPs as well as U7 snRNP involved in histone 3'-end processing (most histone transcripts are not polyadenylated rather their 3' ends are produced by an endonucleolytic cleavage) and U3 and U8 snoRNPs involved in processing of pre-rRNA. It is believed that snRNPs and snoRNPs move through Cajal bodies then on to nuclear speckles or nucleoli respectively.
Gems are found adjacent to Cajal bodies and are characterized by the presence of the survival of motor neurons gene product (SMN) and Gemin 2 (Spector, 2001; Lamond and Sleeman, 2003). Cytoplasmic SMN and Gemin 2 are involved in the assembly of snRNPs and therefore the nuclear pool may play a role in snRNP maturation. Spinal muscular atrophy, a motor neuron disorder, results from reduced levels or a mutation in the SMN protein.
PML bodies are characterized by the presence of PML protein (Strouboulis and Wolffe, 1994; Spector, 2001; Lamond and Sleeman, 2003). PML bodies vary in size from 0.3-1 µm in diameter and a nucleus typically contains 10-30 of these structures (Fig. 2). The primary role of PML bodies remains unclear; but they may play a role in transcriptional regulation and in anti-viral responses. Individuals suffering from acute promyelocytic leukemia (APL) have a translocation in which the PML gene is fused to the gene encoding the alpha-retinoic acid receptor, resulting in the production of a fusion protein. Cells from these individuals exhibit fragmented PML bodies. However, treatment of APL patients with retinoic acid results in cancer remission and the restoration of normal PML body structure.