LIN28-mediated gene regulatory loops synchronize transitions throughout organogenesis

Area of Science:

• Developmental Biology
• Gene Regulation
• Stem Cell Biology

Background:

• Stem cell proliferation and differentiation are controlled by heterochronic genes, including Lin28-RNA-binding proteins (RBPs) and Let-7 microRNAs (miRNAs).
• These conserved genes regulate developmental timing across metazoans.
• While the negative feedback between LIN-28 and Let-7 is well-studied, positive regulatory loops involving Lin28-RBPs and mRNAs in mammalian development are less understood.

Purpose of the Study:

• To investigate positive regulatory loops between mammalian Lin28-RBPs and mRNAs that govern progenitor cell transitions.
• To explore the role of heterochronic factors in ordering spatiotemporal transitions from cell specification to organogenesis.

Main Methods:

• Screening for factors activating human LIN28A and LIN28B promoters using luciferase reporters.
• Utilizing genetic mouse models to study gene function in vivo.
• Analyzing 5' and/or 3' untranslated regions of mRNAs for regulatory sequences.

Main Results:

• Demonstrated positive feedforward loops between Lin28-RBPs and key developmental transcription factors like B-Catenin, Sox2, and Sox9.
• Identified molecular fine-tuning of heterochronic regulation of morphogenesis through position-dependent sequences in untranslated regions of mRNAs.

Conclusions:

• Positive feedforward loops involving Lin28-RBPs and transcription factors play a crucial role in mammalian developmental timing.
• Heterochronic regulation of morphogenesis is modulated by both genetic interactions and precise molecular control within mRNA untranslated regions.