MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary.
The midbrain-hindbrain boundary (MHB) is a long-lasting organizing center in the vertebrate neural tube that is both necessary and sufficient for the ordered development of midbrain and anterior hindbrain (midbrain-hindbrain domain, MH). The MHB also coincides with a pool of progenitor cells that contributes neurons to the entire MH. Here we show that the organizing activity and progenitor state of the MHB are co-regulated by a single microRNA, miR-9, during late embryonic development in zebrafish. Endogenous miR-9 expression, initiated at late stages, selectively spares the MHB. Gain- and loss-of-function studies, in silico predictions and sensor assays in vivo demonstrate that miR-9 targets several components of the Fgf signaling pathway, thereby delimiting the organizing activity of the MHB. In addition, miR-9 promotes progression of neurogenesis in the MH, defining the MHB progenitor pool. Together, these findings highlight a previously unknown mechanism by which a single microRNA fine-tunes late MHB coherence via its co-regulation of patterning activities and neurogenesis.
Leucht
Christoph
C
Department of Zebrafish Neurogenetics, Institute of Developmental Genetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Ingolstädter Landstrasse 1, D-85764 Neuherberg, Germany.
Stigloher
Christian
C
Wizenmann
Andrea
A
Klafke
Ruth
R
Folchert
Anja
A
Bally-Cuif
Laure
L
D000818:Animals; D030801:Animals, Genetically Modified; D019521:Body Patterning / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004625:Embryo, Nonmammalian; D005346:Fibroblast Growth Factors / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000502:physiology*; D008636:Mesencephalon / Q000196:embryology*; D035683:MicroRNAs / Q000494:pharmacology / Q000502:physiology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009716:Numerical Analysis, Computer-Assisted; D020897:Organizers, Embryonic / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D012249:Rhombencephalon / Q000196:embryology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000235:genetics
D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D029961:Zebrafish Proteins; D005346:Fibroblast Growth Factors