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Yang, D. ; Lutter, D. ; Burtscher, I. ; Uetzmann, L. ; Theis, F.J. ; Lickert, H.

miR-335 promotes mesendodermal lineage segregation and shapes a transcription factor gradient in the endoderm.

Development 141, 514-525 (2014)
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Transcription factors (TFs) pattern developing tissues and determine cell fates; however, how spatio-temporal TF gradients are generated is ill defined. Here we show that miR-335 fine-tunes TF gradients in the endoderm and promotes mesendodermal lineage segregation. Initially, we identified miR-335 as a regulated intronic miRNA in differentiating embryonic stem cells (ESCs). miR-335 is encoded in the mesoderm-specific transcript (Mest) and targets the 3'-UTRs of the endoderm-determining TFs Foxa2 and Sox17. Mest and miR-335 are co-expressed and highly accumulate in the mesoderm, but are transiently expressed in endoderm progenitors. Overexpression of miR-335 does not affect initial mesendoderm induction, but blocks Foxa2- and Sox17-mediated endoderm differentiation in ESCs and ESC-derived embryos. Conversely, inhibition of miR-335 activity leads to increased Foxa2 and Sox17 protein accumulation and endoderm formation. Mathematical modeling predicts that transient miR-335 expression in endoderm progenitors shapes a TF gradient in the endoderm, which we confirm by functional studies in vivo. Taken together, our results suggest that miR-335 targets endoderm TFs for spatio-temporal gradient formation in the endoderm and to stabilize lineage decisions during mesendoderm formation.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Endoderm; Foxa2; Gastrulation; Mesendoderm; Mir335; Mouse; Sox17; miR-335; Embryonic Stem-cells; Temporal Pattern-formation; Mouse Embryo; Host Genes; Differential Expression; Caenorhabditis-elegans; Definitive Endoderm; Microrna Biogenesis; Intronic Micrornas; Signaling Pathway
Language english
Publication Year 2014
HGF-reported in Year 2014
ISSN (print) / ISBN 0950-1991
e-ISSN 1477-9129
Journal Development / Company of Biologists
Quellenangaben Volume: 141, Issue: 3, Pages: 514-525 Article Number: , Supplement: ,
Publisher Company of Biologists
Publishing Place Cambridge
Reviewing status Peer reviewed
Institute(s) Institute of Diabetes and Regeneration Research (IDR)
Institute of Diabetes and Obesity (IDO)
Institute of Computational Biology (ICB)
Institute of Stem Cell Research (ISF)
Institute of Bioinformatics and Systems Biology (IBIS)
POF-Topic(s) 30201 - Metabolic Health
30205 - Bioengineering and Digital Health
30204 - Cell Programming and Repair
30505 - New Technologies for Biomedical Discoveries
90000 - German Center for Diabetes Research
Research field(s) Helmholtz Diabetes Center
Enabling and Novel Technologies
Stem Cell and Neuroscience
PSP Element(s) G-502300-001
G-502200-001
G-503800-001
G-500800-001
G-503700-001
G-501900-231
PubMed ID 24449834
DOI 10.1242/dev.104232
WOS ID WOS:000330573500003
Permalink http://dev.biologists.org/content/141/3/514.full.pdf+html
Scopus ID 84892711156
Erfassungsdatum 2014-01-27
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