Lin28: Linking Organ Development and Tumorigenesis in the Kidney

Abstract

Lin28 is a highly conserved RNA binding protein that modifies gene expression via direct binding of mRNAs and by blocking the processing of the let-7 family of microRNAs. In vertebrates, Lin28a and its paralog Lin28b have been implicated in self-renewal of mammalian embryonic stem cells, organismal growth, tissue development and tumorigenesis, however their role in these processes is not fully understood. We discovered that forced expression of Lin28 in developing kidneys in mice results in pathology highly reminiscent of Wilms tumor, the most common pediatric tumor of the kidney. We established that LIN28B is overexpressed in significant percentage of human Wilms tumor and that the LIN28 gene can be activated through chromosomal translocation, firmly linking LIN28 to the pathogenesis of the disease. Subsequent studies reveal that Lin28b/let-7 axis controls the timing and duration of kidney development and manipulation of the pathway represents a therapeutic strategy for enhancing kidney function. Such a strategy holds promise for children suffering from the complications of premature birth and/or intrauterine growth restriction and could have profound effects on long-term health for the individual and the health burden of hypertension and renal failure of the population as a whole. The work in this thesis reveals novel mechanisms underling organ development and tumorigenesis in the kidney and paves the way for a deeper understanding of critical aspects of mammalian development.