LIN28-mediated gene regulatory loops synchronize developmental transitions throughout organogenesis

Precise control of the intervals between self-renewal, proliferation, and differentiation of stem/progenitor cells are coordinated by developmental regulators, comprised of both microRNAs (miRNAs) and proteins, termed heterochronic genes. These heterochronic factors make up a unique subset of evolutionarily conserved genes that regulate the developmental rate and timing of metazoans from worms to mammals. We and others have shown critical roles for the RNA-binding proteins (RBPs) Lin28 during pluripotency, reprogramming, and organogenesis. There has been much investigation into the negative feedback loop between the Lin28-RBPs and the miRNAs– Let-7 during development and disease. Albeit there are fewer investigations into how positive feedback loops between mammalian Lin28-RBPs and mRNAs order mammalian spatiotemporal transitions of progenitors from specification to organogenesis. Screening for factors that activate luciferase reporters of the human LIN28A and LIN28B 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 and ultimately differentiation is not only genetically moderated but also molecularly fine-tuned via position-dependent sequences in the 5’ and/or 3’ untranslated regions.