Kidney development is initiated when the ureteric bud comes in contact with and grows into the metanephric blastema. This sets in motion a series of reciprocal inductive interactions which stimulate: a) a progressive branching of the ureteric bud; b) conversion and differentiation of the blastemal cells into renal tubular epithelial cells with parallel formation of the nephron structure. These events lead ultimately to formation of the complex structure which is the mature kidney. Several growth factor/receptor pairs have been shown to modulate embryonic kidney development, but many more modulators remain to be identified. A role for epidermal growth factor receptor, a member of the family of erbB receptors in this process is currently unclear. Based on preliminary data we hypothesize that erbB3 receptor and its ligand, neuregulin, play important roles in fetal renal development. To test this hypothesis, two sets of experiments will be performed using the mouse as a model developmental system. First, the expression patterns for erbB3 receptor and neuregulin in the developing kidney will be defined using immunohistochemical and molecular biological techniques. If this receptor/ligand pair modulates fetal renal development, then both components must be expressed at appropriate times and places in the kidney to exert an effect. In addition, we will pursue preliminary results suggesting that erbB4, the other neuregulin receptor, is not expressed in the developing kidney at an appropriate time and place to regulate kidney development. Second, the effect of manipulation of erbB3 receptor activity on fetal renal development both in vivo and in vitro will be elucidated by comparing kidney development in vivo in wild type versus erbB3 knockout mice and by examining the effect of neuregulin treatment on fetal renal development of both wild type fetal mouse kidneys and erbB3 knockout fetal mouse kidneys using a fetal kidney organ culture system. Parameters to be examined include the blastema-mediated progressive branching of the ureteric bud, nephrogenesis (as defined by a number of glomeruli), and ureteric bud-mediated induction of metanephric blastemal cells (by examining expression of several markers of induced blastemal cells). These studies will determine unambiguously whether erbB3 receptor activity: 1) can influence fetal renal development; and 2) is required for normal fetal renal development.
