My lab is interested in the role of stem/progenitor cells in mammalian organ development, homeostasis, regeneration and disease. The main focus of the lab is on NOV (CCN3) which we and others have identified as a key regulator of stem/progenitor cells. NOV encodes a multi-domain secreted protein which is associated with the extracellular matrix and acts to mediate and modulate the cell’s response to signaling molecules in the extracellular environment. NOV is a member of a family of proteins, the CCN family, which modulates the activities of extracellular signaling molecules and thereby profoundly influences the behaviour of cells in development, wound healing, tissue homeostasis and in a range of diseases including fibrosis and cancer. We are investigating the role of NOV in regulating stem/progenitor cell proliferation, survival and differentiation in mesodermal and embryonic stem cells in cell culture and in organ development and homeostasis using transgenic and knockout technologies. The aim of our work is to understand how NOV regulates stem/progenitor cell behaviour and the mechanisms by which defects in NOV function lead to disease. As developmental mechanisms involving stem and progenitor cells also underpin organ regeneration and repair, our work also has relevance for greater understanding of these processes.
Differentiation down the osteogenic lineage is promoted in primary embryonic fibroblasts (PEFs) from Novdel3-/- embryos, shown by staining with the osteoblast marker, alkaline phosphatase.
A,B: PEFs from Novdel3-/- embryos; C,D: PEFs from wild type Novdel3+/+ embryos, viewed with (A,C) and without (B,D) phase contrast.
Our work on NOV came out of a long-standing interest of my lab in the developmental basis of kidney disease, which focused on the childhood kidney tumour Wilms’ tumour (or nephroblastoma), as well as on Autosomal Dominant Polycystic Kidney Disease (ADPKD). Deregulated expression of NOV is implicated in the formation of nephroblastomas which are characterized by the abnormal proliferation and differentiation of kidney stem (blastemal cells); it is also deregulated in a variety of other tumours, including musculoskeletal tumours, suggesting a more general involvement in tumourigenesis. We have generated the first targeted Nov mutant (Novdel3) which reveals roles for NOV in development and tissue homeostasis.
Dr Marko Hyvonen, Cambridge
Prof Tariq Enver and Dr Rajeev Gupta, London
Prof Charlie Archer, Swansea
Prof Stewart Fleming, Dundee
Postgraduate Research Student
Nurul Adnin Mohd Azali