Cajal body
Cajal bodies (“Cajal Bodies” (CBs), “Coiled Bodies”) are spherical sub- organelles within the cell nucleus that occur in rapidly multiplying cells such as those in embryos or tumor cells. In contrast to organelles of the cytoplasm , Cajal bodies do not have a membrane to separate their contents from the surrounding caryoplasm . They contain components of RNA processing, their exact function is the subject of current research. They have a diameter of 0.3–1.0 µm and consist of RNA and proteins . In the cell nuclei of mammalian, plant and Drosophila cells, only one or two of these bodies occur on average, while up to 100 CBs occur in the germinal vesicles of the clawed frog .
They are involved in the production of different types of snRNPs , which are small nuclear ribonucleoprotein particles. The Cajal bodies are involved in RNA metabolic processes such as the production, maturation and degradation of snRNPs, processing of histonic mRNA and the maintenance of telomeres . The best known of these processes is the modification and assembly of U-snRNPs, some of which eventually form the spliceosome . Cajal bodies have remained largely unchanged in the course of evolution.
They were first discovered by Santiago Ramón y Cajal in 1903, who called them "auxiliary nuclear bodies" because of their association with the cell nuclei in neuronal cells. They were later rediscovered with electron microscopes and named here as “coiled bodies” because of their shape. Only later were they named after their discoverer.
Research on the Cajal bodies accelerated when it was discovered that the protein p80 / coilin could be used as a marker for these bodies. The interaction of Coilin with other proteins appears to improve the efficiency of several core processes by concentrating their components in the Cajal body.
history
In 1903, Ramón y Cajal discovered in a large number of neurons and in several mammalian species (rabbits, dogs and humans) a sharply defined argyrophilic (silver affine) structure with a diameter of approx. 0.5 µm, which had a homogeneous texture and was free in the caryoplasm seemed to exist. In the same year, Ramón y Cajal published his silver nitrate method with several variants, which enabled him to clearly characterize various intracellular structures - essentially nuclear components and neurofibrils (neurofilaments) - due to their pronounced affinity for silver. Seven years later he published a detailed article on the structure of the cell nucleus in mammalian neurons (El núcleo de las células piramidales del cerebro humano y de algunos mamíferos). In this article, Ramón y Cajal reported on the presence of a new nuclear structure in mammalian neurons, the “auxiliary body”, as well as preliminary data on the structure and organization of the cell nucleus in several neuronal types.
As characterized by Ramón y Cajal, the “auxiliary bodies” attracted little attention until the 1950s, when Murray Barr of the University of Western Ontario and his team focused their interest on the organization of the neural core. They published several papers. They confirmed Ramón y Cajal's observations, performed a quantitative analysis of the frequency of auxiliary bodies in several nerve centers, and reported the rare occurrence of an argyrophilic paranuclear structure in cat neurons.
In 1969, Monneron and Bernhard conducted a study of the core organization of several mammalian cell types. In addition to other RNA-rich core structures, they reported a new nuclear component, which they referred to as “coiled bodies”. Other different names were “internal bodies” in insects (Bier et al. 1967) and nucleolus- associated bodies in plants (Chamberland and Lafontaine 1993). In 1999 there were two publications by Carvalho and Gall , which introduced the nomenclature "Cajal body".
Proteins involved
snRNPs
snRNPs are macromolecular complexes that are required for gene expression. snRNPs store u. a. together to form a spliceosome , which is used to cut introns out of a newly generated RNA.
Researchers quickly realized that Cajal bodies contain a variety of proteins and RNAs that are involved in RNA processing, particularly the snRNAs necessary for splicing (U1, U2, U4, U5, and U6) and the proteins associated with them. Cajal bodies in cell cultures are sensitive to the inhibition of transcription, splicing and snRNP biogenesis. The snRNPs first disappear from the CBs after transcription and splice inhibition, followed by the dissolution of the Cajal body shortly thereafter. This shows that the constant production and recycling of snRNPs are essential for the integrity of the Cajal bodies.
In all species that have been explored to date, the spliceosomal snRNPs are bundled in the Cajal bodies.
Survival of motor neuron - SMN
As the name suggests, SMN is a prerequisite for the function of motor neurons , especially the spinal cord, in mammals . Mutations in the gene for this protein can lead to spinal muscular atrophy . Biochemical studies show that SMN occurs in vertebrate cells in a macromolecular complex made up of SMN itself and several other factors. This complex functions in the cytoplasm as a chaperone for the assembly of the snRNAs with the seven-membered ring of Sm proteins. SMN accompanies the newly manufactured snRNPs as they return to the nucleus, but whether SMN has a specific function in the Cajal body is not known.
Coilin
The coilin protein is one of the most important molecular components of Cajal bodies. After its discovery in HeLa cells, Coilin quickly became a marker for CBs in mammalian cells. Despite its usefulness as a marker for Cajal bodies, relatively little is known about coilin as a protein, particularly what biochemical functions it might have in it.
The human and mouse coilin proteins are similar in size, 62.6 kDa and 62.3 kDa, respectively. Coilin binds to survival motor neuron protein (SMN) and to various Sm and Lsm proteins, suggesting that it contributes to the assembly or modification of snRNPs. It appears that coilin (and the connection of Cajal bodies) favors the interconnection of snRNPs, either by promoting the final ripening process of the snRNPs or by enabling interrelationships between individual snRNPs to form higher-level complexes.
Coilin appears to be essential to the integrity and function of the Cajal body. In the absence of CBs, the same reactions take place with less efficiency in the caryoplasm. This is consistent with the view of the Cajal body as a means of increasing the efficiency of the snRNP assembly by concentrating enzymes and substrates in a region of the karyoplasm. For example, in the three organisms in which coilin mutations have been studied, coilin is required for normal CB formation, but neither coilin nor a typical CB are essential for viability.
In addition to its structural role, Coilin acts as an adhesive to connect the Cajal bodies to the nucleolus.
Sequence of the production of snRNPs
Overview
During the biogenesis of snRNAs to mature snRNPs, the snRNAs have to be transported into the cytoplasm and the created snRNPs then have to be transported back into the cell nucleus.
1) First, the snRNA is transcribed from the DNA using the polymerase II molecule.
2) Now further molecules are attached to the snRNA, which serve as a transport signal. As a result, the snRNA molecule is exported into the cytoplasm through a nuclear pore.
3) In the cytoplasm, Sm proteins bind to the snRNAs with the SMN protein complex. (Sm / LSm proteins are defined by an arrangement in rings of six or seven individual LSm protein molecules and play a variety of different roles in mRNA processing and regulation.) The snRNA is also modified by other enzymes. The core of the snRNP molecule is formed here.
4) The snRNP is transported back into the cell nucleus via a nuclear pore.
5) Further modifications of the snRNP molecule in the Cajal body take place in the cell nucleus. Here z. B. additional specific proteins added. After the final maturation of the snRNP, the molecule is used for the splicing process.
Processes within the Cajal body
Both large and small U-snRNA genes are often found in the vicinity of Cajal nuclear bodies. Several studies have shown that snRNA transcription and the resulting snRNAs are necessary for the association of CBs with the U-snRNA gene. It has been suggested that CBs are involved in the organization of snRNA genes in the nucleus. snRNAs may be linked to the CBs as soon as they are formed. The lack of proteins that are essential for the integrity of CBs results in lower expression of all snRNAs. How exactly CBs improve snRNA expression is currently unclear.
From the fact that coilin is directly associated with snRNAs and could even play a direct role in their processing, one can conclude that CBs are involved in the 3 'end processing of pre-snRNAs. After cleavage at their 3 'end, snRNAs are exported into the cytoplasm via a complex (1). This contains, among other things, the proteins XPO1 and PHAX, both of which are found in CBs. The 5 'end of the snRNA is connected to the complex by the CBC protein (Cap-Binding Complex).
(2) After completion of the phase in the cytoplasm, the newly formed snRNPs of the nucleus return to the nucleus and initially accumulate in CBs. However, the exact molecular signals that bring the unfinished snRNPs to the CBs are unknown. Coilin interacts directly with snRNAs and the Sm proteins and thus possibly serves as a CB target signal. The SART3 protein has been shown to be important for the correct CB localization of U4 and U5 snRNAs. The SMN complex, which interacts with the Sm ring in the cytoplasm, has also been proposed to bring new snRNPs to the CBs by having a domain in the SMN protein interact with coilin.
After importing into the Cajal body, the new snRNA is modified by methylation and isomerization of uridines to pseudouridines . The snRNPs still have to be linked to snRNP-specific proteins. The final step in snRNP maturation is the formation of the spliceable molecules U2- and U4 / U6 / U5-snRNPs (tri-snRPs).
(3) During splicing, the tri-snRNP undergoes a rearrangement that leads to the release of individual snRNPs from the post-splice splice system. However, the exact molecular composition of snRNPs after splicing is not well defined.
(4) The Cajal bodies also appear to be involved in the reassembly of snRNPs after the splicing process. The SMN complex was also found in the cell nucleus (Gems and CBs) and was considered important for snRNP recycling. So it is plausible that the nuclear SMN complex is involved in the repair of damaged Sm rings. This could take place in the CBs. An alternative hypothesis suggests that the SMN complex dismantles the Sm ring during snRNP degradation.
The quality of snRNP formation is evidently controlled at several points along the manufacturing route. First, other proteins are involved in the recognition and breakdown of abnormal snRNAs in the nucleus. However, a molecular mechanism that describes how misfolded snRNAs are recognized is unknown. It has been shown that an additional checkpoint exists which controls the final steps of snRNP maturation, sequesters immature snRNPs and only allows mature particles to enter the splicing reaction.
Telomeres
Another relationship exists between Cajal bodies and the telomeres . For most of the cell cycle, telomerase RNA is only detectable in Cajal bodies. However, in the S phase , when the telomeres are elongated, the telomerase RNA can also be detected in a subset of telomeres. These telomeres contain other components of the telomerase holoenzyme that do not normally accumulate there. In addition, Cajal bodies have been observed to form short-term associations with telomeres during the S phase. These results suggest that specific interactions between Cajal bodies and telomeres occur during telomere elongation.
Gems
The Gemini of Cajal bodies or Gems are found in the vicinity of Cajal bodies. Their name is derived from their constellation of their close "twin" relationship with Cajal bodies. Gems are similar in size and shape to Cajal bodies and are practically indistinguishable under a microscope. In contrast to Cajal bodies, Gems do not contain small nuclear ribonucleoproteins (snRNPs), but the protein SMN. Gems are believed to aid the Cajal bodies in snRNP biogenesis, although microscopic studies have also shown that Cajal bodies and Gems are different manifestations of the same structure. Later studies of ultrastructure have shown that Gems are twins of Cajal bodies. The difference here lies in the coil component: Cajal bodies contain SMN and coilin proteins, and gems contain SMN but not coilin.
Individual evidence
- ↑ a b c d Cajal Bodies and their role in embryogenesis and RNA formation. Retrieved March 2, 2019 .
- ↑ a b c d e David Staněk: Cajal bodies and snRNPs - friends with benefits . In: RNA Biology . tape 14 , no. 6 , June 3, 2017, ISSN 1547-6286 , p. 671-679 , doi : 10.1080 / 15476286.2016.1231359 , PMID 27627834 , PMC 5519240 (free full text) - ( tandfonline.com [accessed March 2, 2019]).
- ^ A b Glenn E. Morris: The Cajal body . In: Biochimica et Biophysica Acta (BBA) - Molecular Cell Research . tape 1783 , no. November 11 , 2008, pp. 2108–2115 , doi : 10.1016 / j.bbamcr.2008.07.016 ( elsevier.com [accessed March 3, 2019]).
- ↑ Miguel Lafarga, Iñigo Casafont, Rocio Bengoechea, Olga Tapia, Maria T. Berciano: Cajal's contribution to the knowledge of the neural cell nucleus . In: Chromosoma . tape 118 , no. 4 , August 2009, ISSN 0009-5915 , p. 437-443 , doi : 10.1007 / s00412-009-0212-x .
- ↑ a b c d Z. Nizami, S. Deryusheva, JG Gall: The Cajal Body and Histone Locus Body . In: Cold Spring Harbor Perspectives in Biology . tape 2 , no. 7 , July 1, 2010, ISSN 1943-0264 , p. a000653 – a000653 , doi : 10.1101 / cshperspect.a000653 ( cshlp.org [accessed March 4, 2019]).
- ↑ a b A. Gregory Matera, Mark R. Frey: Coiled Bodies and Gems: Janus or Gemini? In: The American Journal of Human Genetics . tape 63 , no. 2 , August 1998, p. 317–321 , doi : 10.1086 / 301992 , PMID 9683623 , PMC 1377332 (free full text) - ( elsevier.com [accessed August 11, 2019]).
- ^ A. Gregory Matera: Of coiled bodies, gems, and salmon . In: Journal of Cellular Biochemistry . tape 70 , no. 2 , August 1, 1998, pp. 181–192 , doi : 10.1002 / (SICI) 1097-4644 (19980801) 70: 23.0.CO; 2-K ( wiley.com [accessed August 11, 2019]).
- ↑ Joaquin Navascues, Maria T. Berciano, Karen E. Tucker, Miguel Lafarga, A. Gregory Matera: Targeting SMN to Cajal bodies and nuclear gems during neuritogenesis . In: Chromosoma . tape 112 , no. June 8 , 2004, ISSN 0009-5915 , doi : 10.1007 / s00412-004-0285-5 , PMID 15164213 , PMC 1592132 (free full text).