Nuclear domains

Abstract

The mammalian cell nucleus is a membrane-bound organelle that contains the machinery essential for gene expression. Although early studies suggested that little organization exists within this compartment, more contemporary studies have identified an increasing number of specialized domains or subnuclear organelles within the nucleus (Lamond and Earnshaw,1998; Spector,1993). In some cases, these domains have been shown to be dynamic structures and, in addition, rapid protein exchange occurs between many of the domains and the nucleoplasm(Misteli, 2001). An extensive effort is currently underway by numerous laboratories to determine the biological function(s) associated with each domain. The accompanying poster presents an overview of commonly observed nuclear domains.FIG1The nucleus is bounded by a nuclear envelope, a double-membrane structure, of which the outer membrane is contiguous with the rough endoplasmic reticulum and is often studded with ribosomes. The inner and outer nuclear membranes are fused together in places, forming nuclear poresthat serve in the transit of materials between the nucleus and cytoplasm(Stoffler et al., 1999). The nuclear pore complex has been shown to have a remarkable substructure, in which a basket extends into the nucleoplasm. The peripheral nuclear lamina lies inside the nuclear envelope and is composed of lamins A/C and B and is thought to play a role in regulating nuclear envelope structure and anchoring interphase chromatin at the nuclear periphery. Internal patches of lamin protein are also present in the nucleoplasm (Moir et al.,2000). The cartoon depicts much of the nuclear envelope/peripheral lamina as transparent, so that internal structures can be more easily observed.Within the nucleoplasm, the chromosomes are arranged into chromosome territories, and active genes are thought to reside throughout the surface of the loosely packed territories (Cremer et al.,2000). Homologues do not appear to be paired in interphase mammalian nuclei. In some cell types, a band ofheterochromatin (inactive chromatin) is observed just internal to and associated with the nuclear lamina. In addition, varying amounts of heterochromatin are also observed in more internal nuclear regions. PcG bodies containing polycomb group proteins (i.e. RING1, BMI1 and hPc2) have been observed associated with pericentromeric heterochromatin (Saurin et al.,1998). These domains vary in number (two to several hundred), size (0.2-1.5 μm) and protein composition. It is currently unclear whether these domains are storage compartments or are directly involved in silencing.Pre-mRNA splicing factors are localized in a pattern of 25-50 nuclear speckles as well as being diffusely distributed throughout the nucleoplasm(Spector, 1993). Many of the larger speckles correspond to interchromatin granule clusters (IGCs). These clusters measure 0.8-1.8 μm in diameter and are composed of 20-25-nm diameter particles that appear connected in places. IGCs have been proposed to be involved in the assembly and/or modification of pre-mRNA splicing factors. Nuclear speckles are dynamic structures, and factors are recruited from them to sites of transcription (perichromatin fibrils). Transcription sitesare observed throughout the nucleoplasm, including on the periphery of IGCs,as several thousand foci. In addition to being diffusely distributed, several transcription factors have also been shown to be concentrated in one to three compartments termed OPT (Oct1/PTF/transcription) domains. These domains are 1.0-1.5 μm in diameter and also contain nascent transcripts as well as other transcription factors, but they contain few, if any, factors involved in RNA processing (Grande et al.,1997; Pombo et al.,1998). The OPT domain appears in G1 phase, when it often resides next to nucleoli, and it disappears during S phase. Its function is unknown.In many cell types, pre-mRNA splicing factors are also localized in 1-10Cajal bodies, previously called Coiled Bodies (Gall,2000). These dynamic nuclear bodies are 0.2-1.0 μm in diameter and are thought to play a role in snRNP biogenesis and in the trafficking of snRNPs and snoRNPs. Spliceosomal U1, U2,U4/U6 and U5 snRNPs, as well as the U7 snRNP involved in histone 3′-end processing, and U3 and U8 snoRNPs involved in processing of pre-rRNA, all localize to this structure. It has been proposed that these factors move through the Cajal body en route to nuclear speckles (snRNPs) or nucleoli(snoRNPs). In addition, the Cajal body has been shown to associate with histone loci as well as U1, U2 and U3 gene clusters (Matera,1999).Gems (gemini of Cajal bodies) are found in the nucleoplasm and are coincident with or adjacent to Cajal bodies, depending upon the cell line examined, and they have been characterized by the presence of the survival of motor neurons gene product (SMN) and an associated factor, Gemin2 (Matera,1999). The cytoplasmic pool of SMN and Gemin2 has been implicated in the assembly of sn