PuSH - Publication Server of Helmholtz Zentrum München

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

Development 141, 514-525 (2014)
Publ. Version/Full Text Volltext To article DOI
Free by publisher
Open Access Green as soon as Postprint is submitted to ZB.
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.
Additional Metrics?
Icb_Latent Causes Icb_ML
Edit extra informations Login
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
ISSN (print) / ISBN 0950-1991
e-ISSN 1477-9129
Quellenangaben Volume: 141, Issue: 3, Pages: 514-525 Article Number: , Supplement: ,
Publisher Company of Biologists
Publishing Place Cambridge
Reviewing status Peer reviewed