Regulation of lung endoderm progenitor cell behavior by miR302/367

Abstract

SUMMARYThe 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.

Sox9 plays multiple roles in the lung epithelium during branching morphogenesis

“…After a 30-min pulse of BrdU, we determined the percentage of proximal (Ecad+, Sox2+) and distal (Ecad+, Sox2−) proliferation in the epithelium of control and Sox9 LOF lungs at E14.5. As previously demonstrated (1,(6)(7)(8)(9)(10)(11)14), we confirmed that distal epithelial proliferation was significantly higher than proximal epithelial proliferation in control tissue (40.2% ± 1.7% vs. 29.6% ± 1.7%; P < 0.0005; n = 12) (Fig. 2B and SI Appendix, Fig.…”

“…These saccules will eventually give rise to mature alveoli in the adult mouse (2)(3)(4)(5). Several signaling pathways and transcription factors are known to play roles in branching morphogenesis; however, mechanisms controlling morphogenetic movements in the lungs have only recently started to gain attention (1,(6)(7)(8)(9)(10)(11).…”

Reconstructing dynamic microRNA-regulated interaction networks

“…These include members of the miR-17-92 cluster (25) and the miR302/367 cluster (26). Overexpression of the miR-17-92 cluster promotes cell proliferation and inhibits lung epithelial progenitor cell differentiation.…”

“…Overexpression of the miR-17-92 cluster promotes cell proliferation and inhibits lung epithelial progenitor cell differentiation. GATA6, a key transcription factor for formation of mature alveoli, transcriptionally regulates the miR-302/367 cluster (26). Transgenic mice with no expression of this miRNA cluster had smaller lungs prenatally and displayed reduced cell proliferation.…”

Concise Review: Alchemy of Biology: Generating Desired Cell Types from Abundant and Accessible Cells

“…Some key advances aimed at overcoming these safety concerns have been achieved for the production of iPS cells [11,12,68], and these may be applicable to iTD. Such advances include using nonintegrating viruses (such as adenovirus or episomal plasmid transfection) [69][70][71], treatment of cells with cell-penetrating recombinant reprogramming factor proteins [72], transposon-based systems [73] and the delivery of reprogramming factors in plasmids [74][75][76], repeated transfection of modified mRNA encoding reprogramming factors [77], and miRNAs [78,79].…”