8.17: The Nucleolus

The nucleolus is the most prominent substructure of the nucleus. When it was first discovered, it was considered to be an isolated organelle that forms fibrils and granules. In 1931, the relationship between the nucleolus and chromosomes was first described by Heitz. He observed that the appearance and size of nucleolus varies depending on the stage of the cell cycle. He also noticed constricted regions on different chromosomes clustered together at definite cell cycle stages. These regions, now called nucleolar organizer regions or NORs, are known to contain the genes encoding ribosomal RNA (rRNA).

The structure and number of nucleoli vary depending on the requirement for ribosomal RNA synthesis. Thus, the specific state of differentiation of a cell can be identified from its nucleoli. In aggressive breast cancer cells, the nucleolus becomes 30% larger during tumor progression, which demands heightened ribosomal production. Transversely, in lymphocytes, ribosome synthesis is terminated at the final stage of cell differentiation. Consequently, the nucleoli reduce in size to become tiny fibrillar structures.

The nucleolus consists of three distinct structural regions: the fibrillar center, dense fibrillar component, and granular component. The different regions correspond to the sites of rRNA transcription, processing, and ribosomal assembly, at different stages. The fibrillar centers contain rRNA genes that are transcribed at the boundary separating them from the dense fibrillar component. Processing of precursor rRNAs starts in the dense fibrillar component and extends in the granular component, where the processed rRNAs are assembled with ribosomal proteins. The newly formed pre-ribosomal subunits are then exported to the cytoplasm for further processing into mature ribosomes.

Within the nucleus are several organelles with specialized functions. Of these organelles, the nucleolus is one of the most prominent. 

A nucleolus is the site of ribosomal RNA, or rRNA, transcription and processing and ribosome assembly. Hence it is also referred to as a ‘ribosome producing factory.’

A membraneless organelle, the nucleolus is an aggregate of rRNA genes and the various proteins and RNAs that are required for rRNA transcription and ribosome assembly. These include small nucleolar ribonucleoproteins, or snoRNPs, rRNA-processing enzymes, assembly factors, and partially assembled ribosomes. 

In eukaryotes, three rRNA genes, 18S, 5.8S, and 28S, are encoded by a single transcription unit. This transcription unit is tandemly repeated in the form of arrays in one to several chromosomes. 

The chromosomal regions which contain these rRNA gene clusters are known as ‘nucleolar organizer regions’, or N-O-Rs, and these are the regions around which the organization of nucleolus takes place. 

As a cell transits between the two major cell cycle stages, interphase and mitosis or M-phase, its requirement of protein synthesis changes drastically. 

It is high during interphase, becomes low during most of M phase, and becomes high again as the cell re-enters interphase.  

The size of the nucleolus, which reflects the number of ribosomes that a cell is producing, varies greatly during these cell cycle phases. During interphase, the nucleolus exists as a single large entity. 

At this stage, the chromosomes exist in a decondensed state and the NOR regions contribute DNA in extended, open loops inside the nucleolus. 

As the cell enters M phase, the chromosomes begin to condense and the nucleolus fragments into multiple smaller nucleoli. 

As mitosis progresses further, the pattern continues. The nucleoli gradually decrease in size and finally disappear. At the end of cell division, during telophase, the chromosomes start to decondense and tiny nucleoli begin to emerge. 

As M phase progresses further, the nucleoli progressively merge, through a process called nucleolar fusion. They first coalesce into larger nucleoli, and then into a single, large nucleolus as the cell enters interphase again.