Regulation of lung endoderm progenitor cell behavior by miR302/367

• DOI: 10.1242/dev.061762
• Publication Date: 2011-02-25T02:53:24Z
• Authors: Ying Tian; Yuzhen Zhang; Laura Hurd; Sridhar Hannenhalli; Feiyan Liu; Min Min Lu; Edward E. Morrisey
• Keywords: 0301 basic medicine; Chromatin Immunoprecipitation; Reverse Transcriptase Polymerase Chain Reaction; Stem Cells; Blotting, Western; Endoderm; Gene Expression Regulation, Developmental; Cell Differentiation; Mice, Transgenic; Mice; MicroRNAs; 03 medical and health sciences; GATA6 Transcription Factor; Animals; Lung; Cell Proliferation

The temporal and spatial control of organ-specific endoderm progenitor development is poorly understood. miRNAs affect cell function by regulating programmatic changes in protein expression levels. We show that the miR302/367 cluster is a target of the transcription factor Gata6 in mouse lung endoderm and regulates multiple aspects of early lung endoderm progenitor development. miR302/367 is expressed at early stages of lung development, but its levels decline rapidly as development proceeds. Gain- and loss-of-function studies show that altering miR302/367 expression disrupts the balance of lung endoderm progenitor proliferation and differentiation, as well as apical-basal polarity. Increased miR302/367 expression results in the formation of an undifferentiated multi-layered lung endoderm, whereas loss of miR302/367 activity results in decreased proliferation and enhanced lung endoderm differentiation. miR302/367 coordinates the balance between proliferation and differentiation, in part, through direct regulation of Rbl2 and Cdkn1a, whereas apical-basal polarity is controlled by regulation of Tiam1 and Lis1. Thus, miR302/367 directs lung endoderm development by coordinating multiple aspects of progenitor cell behavior, including proliferation, differentiation and apical-basal polarity.