The current issue of the journal Nature published a scientific research by the scientists at the Stowers Institute for Medical Research. It reports a competition between two proteins, Bam and COP9, for balancing the self-renewal and differentiation functions of ovarian germline stem cells (GSCs) in fruit flies (Drosophila melanogaster).
From fruit flies to human beings, all the adult organisms contain adult stem cells. Some of these cells renew via cell division while others differentiate into specialized cells. These specialized cells replace worn out or damaged organs and tissues. In order to develop therapies to regenerate diseased, injured or aged tissue, it is important to understand the molecular mechanisms that control the balance between self-renewal and differentiation.
According to the researchers, Bam is the master differentiation factor in the Drosophila female GSC system. It must inactivate the functions of self-renewing factors in order to carry out the switch from self-renewal to differentiation. Plus it must activate the functions of differentiation factors as well.
Bam is encoded by the gene with the unusual name of bag-of-marbles. It is expressed at high levels in differentiating cells and very low levels in GSCs of fruit flies.
The COP9 signalosome (CSN) is among the self-renewing factors targeted by Bam. It is an evolutionarily conserved, multi-functional complex. Furthermore, it contains eight protein sub-units (CSN1 to CSN8). The research team and the collaborators discovered that Bam and the COP9 sub-unit i.e. CSN4 have opposite functions in regulating the fate of GSCs in female fruit flies.
Bam can potentially switch COP9 function from self-renewal to differentiation by seizing and upsetting CSN4. It directly binds to CSN4 and prevents its association with the seven other components of COP9 through protein competition. Note that CSN4 is the only sub-unit of COP9 that can interact with Bam.
What does the study say?
The research team used a combination of genetic, molecular, genomic and cell biological approaches to investigate GSCs as well as somatic stem cells of fruit flies. Thus, the study offers a novel way for Bam to carry out the switch from self-renewal to differentiation.
The research reports that CSN4 is the only one of the eight sub-units that is not involved in the regulation of GSC differentiation of female fruit flies. These opposite effects of CSN4 and the other CSN proteins are accredited to the sequestration of CSN4 by Bam that allows the other CSN proteins to have functions that promote differentiation.
Drosophila female is a powerful model system for studying adult stem cells. It has GSCs revealing many novel regulatory strategies which have been later confirmed to be generally true. The researchers of the study are hoping to identify the molecular mechanisms in their future studies. These mechanisms include the ones enabling COP9 to promote GSC self renewal with CSN4 and to enhance differentiation without CSN4.
The findings published in Nature build upon previous research to understand the molecular mechanisms, influencing GSC self-renewal and differentiation.
According to the previous studies, Bam is required to repress the expression of E-cadherin. It is a cell-to-cell adhesion molecule that binds adult stem cells to their tissue niches and promotes GSC self-renewal. Moreover, Bam inactivates the function of the eukaryotic initiation factor-4A (eIF4A). It is another promoter of GSC self-renewal that plays a role in gene expression. Other studies have also revealed that Bam also suppresses the expression of the protein called “Nanos.” Similar to COP9, Nanos is regarded as an essential protein to establish and maintain self-renewing GSCs in female fruit flies.