LIN28-mediated gene regulatory loops synchronize transitions throughout organogenesis

Control of the intervals between proliferation and differentiation of stem/progenitor cells is coordinated by developmental regulators, comprised of both microRNAs (miRNAs) and proteins, termed heterochronic genes. The heterochronic factors, Lin28-RNA-binding proteins (RBPs) and the miRNAs-<i>Let-7,</i> comprise a unique subset of evolutionarily conserved genes that regulate the developmental timing of metazoans, from worms to mammals. While there has been much investigation into the reciprocal negative feedback loop between LIN-28 and <i>Let-7</i> during fetal development and cancer. Few have investigated how positive regulatory loops between the mammalian Lin28-RBPs, and mRNAs order spatiotemporal transitions of progenitors from specification to organogenesis. Screening for factors that activated luciferase reporters of the human <i>LIN28A</i> and <i>LIN28B</i> promoters, in combination with genetic mouse models, we demonstrate positive feedforward loops between key developmental transcription factors such as B-Catenin, Sox2, Sox9, and Lin28-RBPs. Furthermore, we demonstrate heterochronic regulation of morphogenesis is not only genetically modulated but also molecularly fine-tuned via position-dependent sequences in the 5' and/or 3' untranslated regions.