Philip Jones - Overview

Stem cells maintain tissues in adult life, and are regulated so that they generate exactly the right number of differentiating cells to balance cell loss from the tissue. We are investigating factors that regulate the decision of adult stem cells to differentiate or self-renew. We have been focusing on the Notch pathway, which has been shown to regulate stem cell fate in several organs. In cancer the normal controls of stem cell differentiation are destroyed, and activated Notch mutants are found in several forms of cancer. By studying the way Notch alters stem cell behaviour we aim to define how the malignant stem cell evades the signals instructing it to differentiate.

Using primary human epidermal cell cultures, we are exploring the relationships between Notch activation, which drives epidermal stem cell differentiation, and the signalling pathways that maintain stem cells in an undifferentiated state. We are also investigating the effect of Notch in vivo using a novel genetic targeting method to introduce mutants of Notch into stem cells in the model system intestine.

In order to understand the molecular basis of Notch signalling we are studying Notch target genes. Hes6 is a transcription factor that is homologous to a family of known Notch targets. Hes6 is expressed in developing muscle, but its expression is lost from adult muscle. Overexpression of Hes6 increases size of the developing muscle compartment in Xenopus embryos, but the muscle that is produced fails to differentiate. A block of differentiation also occurs when Hes6 is expressed in cultured myoblasts. We are analysing the expression of Hes6 in muscle tumours and characterising the molecular basis of its activity.