A functional genomics approach to PDGF and pericyte biology

Abstract

The rapid expansion of genome sequence data demands for increased efforts and speed concerning functional analysis of gene products. Two approaches to such analysis, namely transgenic technologies and analysis of gene expression have successfully been used to study functions of gene products in complex organisms, such as mammals. In this thesis I present functional analyses of platelet-derived growth factors (PDGFs) during development using these two approaches. The PDGF family has four members, PDGF-A-D, and their functions in vivo have been extensively studied with transgenic techniques. Mice lacking the expression of PDGF-A exhibit defects in multiple tissues, including lung, gut and brain. This thesis presents novel findings demonstrating the importance of PDGF-A also in the development of skin and testis. It gives further evidence for PDGF-A as an important regulator of the proliferation of mesenchymal progenitor cells. Mice lacking PDGF-A have a reduced number of such cells in both the skin and in the testis, leading eventually to abnormalities in skin and hair and to testicular defects including a loss of Leydig cells and arrest of spermatogenesis. Mice lacking PDGF-B or its receptor PDGF-Rb show abnormal development of the vascular system resulting in microaneurysms and bleedings. These defects are due to the lack of vascular smooth muscle cells and pericytes surrounding the endothelial tube in blood vessels. Pericytes are found in capillaries and their functions have long been debated. We have used mice lacking PDGF-B or PDGF-Rb to identify genes specifically expressed in pericytes. Analysing the transcriptome of pericytes will reveal information about the intracellular signalling in pericytes and about their communication with other cells. Such analyses may lead to the identification of new drug targets in diseases involving pericytes and blood vessel formation.