Cell Division versus Differentiation in Development and Disease.
University of Cambridge
Department of Oncology
University of Cambridge
Hutchison/MRC Research Centre (Box 197)
Cambridge Biomedical Campus
CB2 0XZ, United Kingdom
Mechanisms that link the cell cycle and differentiation are poorly understood, and still less is known about how developmental cues are linked to cell cycle exit. Our laboratory is interested in understanding the coordination of cell proliferation with cell fate determination and differentiation in the early Xenopus frog embryo as well as in ES cells and mouse models. This image on the right is a blastula stage Xenopus embryo showing multiple, synchronously dividing cells. We focus particularly on development of the embryonic nervous system, along with differentiation of endocrine lineages in the gut and pancreas, where the decision to divide or differentiate is controlled by the activity of proneural transcription factors. Recently, we have been investigating links between the core cell cycle machinery and mechanisms of differentiation. We see that cell cycle components directly control several modes of post-translational regulation of these proneural transcription factors, which in turn, regulates the balance between precursor cell maintenance and differentiation.
Ongoing work in the lab aims to explore cell cycle-regulated control of progenitor maintenance and differentiation in more detail using both in vitro biochemical and molecular assays and in vivo models. Cancer cells often divide precociously and lose differentiated characteristics. Our work in normal embryonic development will help us to determine how cells stop dividing and adopt a differentiated fate, and, will allow us to understand more fully how cells lose their differentiated phenotype and re-enter the cell cycle precociously during tumourigenesis. We are currently attempting to manipulate these processes to promote cancer cell differentiation to effect remission, particularly in neurologically-derived tumours such as neuroblastoma and glioblastoma. Moreover, we are using our findings to develop more efficient protocols to potentiate stem cell differentiation, with the aim of use for replacement therapies in diseases such as Parkinson's and diabetes. The image on the right shows embryonal carcinoma cancer cells can be induced to differentiate into neurons in vitro by expression of a proneural transcription factor that has been mutated so it can no longer be phosphorylated by cyclin-dependent kinases. GFP marks cells expressing the proneural protein, while a marker of neuronal differentiation is detected in red.