During development from a fertilised egg to an entire organism, for example a human or a mouse, a single cell must proliferate very extensively and retain the ability to differentiate into mature cell types. At each step of development transient stem cell populations provide a reservoir for proliferation. One can easily see that if too many cells were to differentiate at an early stage of development, then there would be insufficient cells for the subsequent steps in development. Conversely, if proliferation of the stem cell population proceeded unchecked, it would be impossible for normal organogenesis to take place. Not surprisingly, many of the proteins promoting rapid cell proliferation during development are also involved in the pathogenesis of cancer.
The aim of my laboratory is to understand how the balance between proliferation and differentiation of stem cells is maintained. We are primarily studying this process in development of the central nervous system, particularly in the progenitor cell population of the cerebral cortex, but also in other stem cell populations, such as haematopoietic stem cells. We have identified several genes that regulate different aspects of stem cell biology. By comparing the action of these genes in different stem cell populations we determine common underlying features of stem cell biology.
NHMRC Elizabeth Blackburn Fellowship - Biomedical,
Award for the best doctoral thesis at the School of Veterinary Medicine Hannover, Germany, Erich Aehnelt-Memorial Award,
Available for supervision
Developmental Biology Project Details:
The genetic material together with histones and other associated proteins is organised into chromatin. Chromatin modifications regulate gene expression and cell fate. Many chromatin modifying complexes contain plant homeodomain (PHD) proteins. The importance of PHD proteins is demonstrated by their role in disorders ranging from mental retardation to cancer. For instance, deletion of a PHD finger of the histone methyltransferase mixed lineage leukaemia (MLL) causes T-cell acute lymphoblastic leukaemia.
Although mutations in PHD proteins are known to cause severe human diseases, the molecular and cellular function of many PHD proteins is unknown. This project will determine the function of one of these important proteins and and uncover new mechanisms and molecules involved in gene and chromatin regulation, which may serve as new drug discovery targets.
Mutations of the PHD finger 6 (PHF6) gene cause the Börjeson-Forssman-Lehmann mental retardation and, remarkably, are found in 20% of T-cell lymphoblastic leukaemia cases. The essential role played by PHF6 in the brain is clear from the devastating effect that mutations of the PHF6 gene have on affected individuals, yet we do not know the function of PHF6 at the cellular or molecular level.
This project will examine the cellular and molecular function of PHF6 using methods such as chromatin immunoprecipitation, RNA sequencing expression profiling, RT-qPCR, northern blotting, in situ hybridisation, immunohistochemistry, immunoblotting, DNA synthesis assays, terminal deoxynucleotidyl transferase end labelling, fluorescence-activated cell sorting, and proliferation, survival, migration and differentiation assays.
We hypothesise that PHF6 is required for normal development of the brain, and that PHF6 deficiency affects chromatin modifications