Investigating the endocrine and paracrine roles of the imprinted Igf2 gene in growth, development and metabolism (360G-Wellcome-102355_Z_13_A)

Insulin-like growth factor 2 is major regulator of growth in mammals. It is produced at high levels inside cells and rapidly secreted into the extracellular milieu and circulatory system, thus acting as paracrine and endocrine signals for cellular proliferation, organ and whole body growth. The mechanisms which govern these multiple actions are poorly understood. We recently found that the pancreatic connective tissue (or mesenchyme) is a reservoir of Igf2 that regulates both exocrine and endocrine growth during early development. The major goals of my project are to elucidate how mesenchymal Igf2 promotes growth of the whole pancreas and to contribute to our understanding of Igf2 as an endocrine signal. Specifically, I will test the hypotheses that Igf2 binding to Igf1r in pancreatic mesenchyme is required for paracrine growth signalling, and that fetal mesenchyme is a major source of circulating Igf2. My project takes advantage of precision genetics facilitated by access to unique conditional mouse models of loss and gain of function for Igf2, allied to cell-type specific transcriptomic analysis and whole-body physiologicalphenotyping. Investigations into cross-talk mechanisms between cell types that drive systemic growth are likely to provide novel insights about growth regulatory pathways and metabolic diseases such as diabetes.