Science for Health
Sex determination in mammals is being studied as a system to understand how decisions of cell fate are reached during embryogenesis. Earlier work in the Division identified Sry as the testis determining gene. Sry is expressed briefly in the developing gonad consistent with it acting as a switch giving Sertoli rather than follicle cell differentiation from a common precursor cell type. We are studying additional non-Y genes implicated in sex determination from mutational studies in humans or mice such as Sox9, Dax1 and Dmrt1 and investigating the lineage relationships amongst the cell types comprising the gonad. The aim is to understand the pathway of gene activity that begins with Sry and leads to male rather than female development. The research on Sry led to the discovery of related genes whose protein products have similar DNA binding properties. These Sox genes also seem to be involved in decisions of cell fate, for example in the nervous system. In this context they largely mark the undifferentiated neuronal precursors. Consequently, the genes may help to investigate the properties of neural stem cells which could eventually be used in cell based therapeutic approaches to treat disease or trauma of the CNS. In addition, we have found that the genes play critical roles in the development of the pituitary and sensory systems, notably the eye and inner ear.
In addition to the testis determinant Sry, the mammalian Y chromosome carries a number of other genes that are postulated to have a role in spermatogenesis. By studying male and female mice with variant Y chromosome complements, together with further manipulations by transgenesis, we have identified four genetically separable Y functions in spermatogenesis, one of which has been ascribed to Eif2s3y. Our studies have also shed light on the molecular basis of the transcriptional repression of the X and Y chromosomes during male meiosis – termed Meiotic Sex Chromosome Inactivation (MSCI). We have found that MSCI is mediated by the tumour suppressor proteins BRCA1 and ATR, and that MSCI is a special example of a more general silencing mechanism whose purpose is to eliminate gametes in which homologous chromosomes have failed to pair.
Aside from its function in MSCI, ATR, together with the related kinase ATM, plays an essential role in ensuring the fidelity of genome duplication and segregation in organisms ranging from yeast to human. Failure to carry out these events in an accurate manner leads to genome instability, cell death, and cancer. Utilising a powerful model organism, Saccharomyces cerevisiae (budding yeast), we are investigating the mechanism by which Mec1, the orthologue of Atr, regulates DNA replication, meiotic recombination, and DNA repair. The specific goal is to identify genetic partners of Mec1 in regulating DNA replication. Molecular biology, genetics, and cytological approaches are being utilized for this study.
Budding yeast also serves as a model organism to study molecular mechanisms of eukaryotic cell cycle regulation and in particular the regulation of mitosis. We are using a combined biochemical approach to determine the mechanisms for correctly localising the mitotic spindle so that the duplicated chromosomes are partitioned equally between the dividing cells. Mechanisms such as this protect against changes in chromosome number, a frequent contributory factor to malignant transformation in higher eukaryotes. In addition, there may be important parallels between the asymmetric mother and daughter system of yeast cell division and the asymmetric divisions of differentiating cells.
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