Hox gene found to influence germline stem cell niche
Researchers from Heidelberg have cast light on a basic regulatory mechanism of stem cell differentiation. They were able to show that the Hox transcription factor Abd-B is critical to stem cell niche function in the Drosophila testis.
The Hox genes, which were originally discovered in Drosophila, are perhaps the most important genetic tools used in modern developmental biology (see article entitled “The discovery of homeotic genes”). Drosophila has eight Hox genes. They control the development of the body plan of the fly embryo along the anterior-posterior axis and are clustered into two complexes on different chromosomes. They are lined up on the DNA in exactly the same order as the body segments are arranged along the head-tail axis. All Hox genes are 180 bp long and encode a 60 amino acid long DNA-binding domain, which is known as the homeobox. The products of the Hox genes are transcription factors, which can act as repressors or activators of numerous genes involved in the morphogenesis and differentiation of the body segments. The discovery that very similar, homologous Hox gene clusters control the development of organisms, including humans, species that are rather different from Drosophila, caused a sensation.
In the thirty years since they were discovered, countless researchers have closely studied the Hox genes and the morphogenetic processes they regulate. However, little is known about the Hox-regulated genes, their cell type-specific gene products and their target molecules; the cellular mechanisms of Hox-dependent morphogenesis are also still poorly understood. Various investigations have brought new insights.
Genome-wide investigation of the regulatory Hox networks
Prof. Dr. Ingrid Lohmann and her team at the Centre for Organismal Studies (COS) at the University of Heidelberg are studying the effect of Hox proteins on the early development of Drosophila using genomic, genetic, molecular and biochemical methods along with complex computer analyses and simulations. The researchers from Heidelberg are using this integrative approach to study all aspects of the Hox-dependent regulatory networks and hundreds of Hox-regulated genes in the Drosophila genome. Using functional analyses, the researchers have been able to assess the relationship between the genes and developmental processes such as the diversification of the nervous system as well as the maintenance and differentiation of stem cells. The objective now is to describe the Hox gene-regulated processes both quantitatively and mechanistically.
Ingrid Lohmann’s Developmental Biology research group at COS, which is also a member of the CellNetworks cluster of excellence at Heidelberg University, has discovered a large number of different cell type-specific transcription regulators that, in a precise temporal and spatial pattern, determine the gene expression pattern in the early development of Drosophila flies in cooperation with the Hox proteins. The researchers’ investigations have shown that the regulation of the Hox-dependent target genes is not only down to the binding of Hox genes and a handful of cofactors to the DNA, but that it is also influenced by the finely tuned interaction between other co-regulators and the aforementioned genes and factors. Using computer models and experimental in vivo approaches such as chromatin immunoprecipitation DNA sequencing, the researchers from Heidelberg have identified hundreds of elements in the Drosophila genome that are influenced by Hox master genes.
Correct positioning of the germline stem cell niche
In their recently published paper in the journal “Developmental Cell”, Lohmann and her team have shown in Drosophila how a Hox gene regulates the function of the germline stem cell niche, which is required for the formation of sperm. The differentiation of germline cells – sperm and egg cells – is one of the most fundamental features of multicellular organisms. The researchers’ investigations were part of the cooperative research centre “Maintenance and differentiation of stem cells in development and disease” (CRC 873; spokesperson: Prof. Dr. Anthony D. Ho, Medical Hospital, Department of Internal Medicine V) at the University of Heidelberg. They have been able to show that the Hox transcription factor Abd-B (which in Drosophila morphogenesis controls the development of the last four abdominal segments; see figure) is crucial for the maturation of sperms from their precursor cells in the testis of Drosophila.
The expression of Abd-B in immature spermatocytes leads to the correct positioning of the germline stem cell niche – the microenvironment – in the testis, which stabilises and regulates the activity of the stem cells. In somatic cyst cells, which surround the germ cells during spermatogenesis, the Abd-B transcription factor regulates a structural protein known as integrin. This protein is firmly attached to the cell membrane of cyst cells and binds the precursor cells of the sperm. Abd-B also controls other critical properties, including the correct orientation of the centrosomes during cell division and the division rate of the germline stem cells. If Abd-B is mutated, the niche – and the stem cells located within – lose their position in the testis. This damages their function, which in turn causes the germline cells to divide incorrectly. This then causes the formation of prematurely aged sperm. “Our knowledge of the function of Abd-B helps us to have a better understanding of how these processes are regulated in higher organisms, including humans,” explains Ingrid Lohmann.
Over the last few years, it has become increasingly clear that the stem cell niche plays a key role in the maintenance, self-renewal and functional stability of stem cells. To fulfil the promise of stem cell therapy, i.e. the use of stem cells to treat previously incurable diseases, it is important to gain a detailed understanding of stem cells and their interaction with their environment. While testicular germline stem cells only form new sperm, stem cell researchers over the last few years have succeeded in producing germline derived pluripotent stem cells (gPS cells) in mice, which could potentially replace the ethically highly controversial embryonic stem cells as a source of body cells for use in stem cell therapy.
F. Papagiannouli, L. Schardt, J. Grajcarek, N. Ha, I. Lohmann: The Hox Gene Abd-B Controls Stem Cell Niche Function in the Drosophila Testis. Developmental Cell, Vol 28. Iss 2, 189-202 (27 January 2014), doi: 10.1016/j.devcel.2013.12.016
Prof. Dr. Ingrid Lohmann
Centre for Organismal Studies
Tel.: +47 (0)6221 54-51312