miRNAs and morphogen gradients.

Morphogens induce biological diversity by operating in a dose-dependent manner. Here we review recent evidences indicating that microRNAs (miRNAs) are ideally suited to serve the morphogen cause. miRNAs regulate the establishment of morphogen gradients, including TGFβ, Wnt and other growth factors by acting on their secretion, distribution and clearance. miRNA are also critical in receiving cells, establishing context-dependency and threshold responses. Moreover, miRNAs contributes to gene networks that transform the graded activity of a morphogen into robust cell fate decisions. Finally, we discuss in the perspective section the implication of the new ceRNA hypothesis for morphogen biology.

[1]  Scott Barolo,et al.  Three habits of highly effective signaling pathways: principles of transcriptional control by developmental cell signaling. , 2002, Genes & development.

[2]  A. van Oudenaarden,et al.  MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. , 2007, Molecular cell.

[3]  W. Bushman.  Hedgehog Signaling in Development and Cancer , 2007 .

[4]  Justin J. Cassidy,et al.  A MicroRNA Imparts Robustness against Environmental Fluctuation during Development , 2009, Cell.

[5]  A. Schier,et al.  Morphogen gradients: from generation to interpretation. , 2011, Annual review of cell and developmental biology.

[6]  Jingyuan Deng,et al.  Probing intrinsic properties of a robust morphogen gradient in Drosophila. , 2008, Developmental cell.

[7]  J. Schlessinger,et al.  Cell Signaling by Receptor Tyrosine Kinases , 2000, Cell.

[8]  U. Alon.  Network motifs: theory and experimental approaches , 2007, Nature Reviews Genetics.

[9]  Lea Goentoro,et al.  Evidence that fold-change, and not absolute level, of beta-catenin dictates Wnt signaling. , 2009, Molecular cell.

[10]  D. Bartel.  MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[11]  C. Stigloher,et al.  MicroRNA-9 directs late organizer activity of the midbrain-hindbrain boundary , 2008, Nature Neuroscience.

[12]  E. O’Shea,et al.  Noise in protein expression scales with natural protein abundance , 2006, Nature Genetics.

[13]  Thomas Thum,et al.  miR-212 and miR-132 are required for epithelial stromal interactions necessary for mouse mammary gland development , 2010, Nature Genetics.

[14]  A. Schier.  Nodal signaling in vertebrate development. , 2003, Annual review of cell and developmental biology.

[15]  Raphael Kopan,et al.  The Canonical Notch Signaling Pathway: Unfolding the Activation Mechanism , 2009, Cell.

[16]  David A. Orlando,et al.  Master Transcription Factors Determine Cell-Type-Specific Responses to TGF-β Signaling , 2011, Cell.

[17]  J. Gurdon,et al.  Morphogen gradient interpretation by a regulated trafficking step during ligand-receptor transduction. , 2005, Genes & development.

[18]  C. Niehrs.  Regionally specific induction by the Spemann–Mangold organizer , 2004, Nature Reviews Genetics.

[19]  M. Oelgeschläger,et al.  The establishment of spemann's organizer and patterning of the vertebrate embryo , 2000, Nature Reviews Genetics.

[20]  D. Bartel,et al.  The impact of microRNAs on protein output , 2008, Nature.

[21]  C. Bökel,et al.  Generation and interpretation of FGF morphogen gradients in vertebrates. , 2013, Current opinion in genetics & development.

[22]  Holger Knaut,et al.  miRNA regulation of Sdf1 chemokine signaling provides genetic robustness to germ cell migration , 2011, Nature Genetics.

[23]  P. Swain,et al.  Stochastic Gene Expression in a Single Cell , 2002, Science.

[24]  A. Schier,et al.  Target Protectors Reveal Dampening and Balancing of Nodal Agonist and Antagonist by miR-430 , 2007, Science.

[25]  D. Harrison,et al.  A gradient of JAK pathway activity patterns the anterior-posterior axis of the follicular epithelium. , 2003, Developmental cell.

[26]  Erez Raz,et al.  Control of Chemokine-Guided Cell Migration by Ligand Sequestration , 2008, Cell.

[27]  J. Rinn,et al.  Non-coding RNAs as regulators of embryogenesis , 2011, Nature Reviews Genetics.

[28]  James E Ferrell,et al.  Signaling motifs and Weber's law. , 2009, Molecular cell.

[29]  Mads Kærn,et al.  Noise in eukaryotic gene expression , 2003, Nature.

[30]  A. Joyner,et al.  Otx2, Gbx2 and Fgf8 interact to position and maintain a mid-hindbrain organizer. , 2000, Current opinion in cell biology.

[31]  I. Stamenkovic,et al.  Cell surface-localized matrix metalloproteinase-9 proteolytically activates TGF-beta and promotes tumor invasion and angiogenesis. , 2000, Genes & development.

[32]  C. Hill,et al.  Tgf-beta superfamily signaling in embryonic development and homeostasis. , 2009, Developmental cell.

[33]  R. Russell,et al.  Animal MicroRNAs Confer Robustness to Gene Expression and Have a Significant Impact on 3′UTR Evolution , 2005, Cell.

[34]  Noam Shomron,et al.  Canalization of development by microRNAs , 2006, Nature Genetics.

[35]  S. Cohen,et al.  MicroRNAs and gene regulatory networks: managing the impact of noise in biological systems. , 2010, Genes & development.

[36]  Uyen Tran,et al.  MicroRNA control of Nodal signalling , 2007, Nature.

[37]  J. Y. Kuwada,et al.  SUMMARY bHLH transcription factor Her 5 links patterning to regional inhibition of neurogenesis at the midbrain-hindbrain boundary , 2003 .

[38]  David H. Sharp,et al.  Canalization of Gene Expression in the Drosophila Blastoderm by Gap Gene Cross Regulation , 2009, PLoS biology.

[39]  Stefano Piccolo,et al.  MicroRNA control of signal transduction , 2010, Nature Reviews Molecular Cell Biology.

[40]  H. Meinhardt,et al.  miRNA-mediated feedback inhibition of JAK/STAT morphogen signaling establishes a cell fate threshold , 2011, Nature Cell Biology.

[41]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[42]  Hervé Seitz,et al.  Redefining MicroRNA Targets , 2009, Current Biology.

[43]  Lynn Doucette-Stamm,et al.  A C . elegans genome-scale microRNA network contains composite feedback motifs with high flux capacity , 2008 .

[44]  C. Nelson,et al.  Mammary branch initiation and extension are inhibited by separate pathways downstream of TGFβ in culture. , 2011, Experimental cell research.

[45]  W. Bialek,et al.  Probing the Limits to Positional Information , 2007, Cell.

[46]  G. Goodall,et al.  The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1 , 2008, Nature Cell Biology.

[47]  George Q. Daley,et al.  Lineage Regulators Direct BMP and Wnt Pathways to Cell-Specific Programs During Differentiation and Regeneration, , 2011 .

[48]  M. F. Shannon,et al.  A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. , 2008, Cancer research.