PMCC PMCC

Search tips
Search criteria

Advanced
Results 1-11 (11)
 

Clipboard (0)
None

Select a Filter Below

Journals
Year of Publication
1.  The combination of transcriptomics and informatics identifies pathways targeted by miR-204 during neurogenesis and axon guidance 
Nucleic Acids Research  2014;42(12):7793-7806.
Vertebrate organogenesis is critically sensitive to gene dosage and even subtle variations in the expression levels of key genes may result in a variety of tissue anomalies. MicroRNAs (miRNAs) are fundamental regulators of gene expression and their role in vertebrate tissue patterning is just beginning to be elucidated. To gain further insight into this issue, we analysed the transcriptomic consequences of manipulating the expression of miR-204 in the Medaka fish model system. We used RNA-Seq and an innovative bioinformatics approach, which combines conventional differential expression analysis with the behavior expected by miR-204 targets after its overexpression and knockdown. With this approach combined with a correlative analysis of the putative targets, we identified a wider set of miR-204 target genes belonging to different pathways. Together, these approaches confirmed that miR-204 has a key role in eye development and further highlighted its putative function in neural differentiation processes, including axon guidance as supported by in vivo functional studies. Together, our results demonstrate the advantage of integrating next-generation sequencing and bioinformatics approaches to investigate miRNA biology and provide new important information on the role of miRNAs in the control of axon guidance and more broadly in nervous system development.
doi:10.1093/nar/gku498
PMCID: PMC4081098  PMID: 24895435
2.  Shh/Boc Signaling Is Required for Sustained Generation of Ipsilateral Projecting Ganglion Cells in the Mouse Retina 
Sonic Hedgehog (Shh) signaling is an important determinant of vertebrate retinal ganglion cell (RGC) development. In mice, there are two major RGC populations: (1) the Islet2-expressing contralateral projecting (c)RGCs, which both produce and respond to Shh; and (2) the Zic2-expressing ipsilateral projecting RGCs (iRGCs), which lack Shh expression. In contrast to cRGCs, iRGCs, which are generated in the ventrotemporal crescent (VTC) of the retina, specifically express Boc, a cell adhesion molecule that acts as a high-affinity receptor for Shh. In Boc−/− mutant mice, the ipsilateral projection is significantly decreased. Here, we demonstrate that this phenotype results, at least in part, from the misspecification of a proportion of iRGCs. In Boc−/− VTC, the number of Zic2-positive RGCs is reduced, whereas more Islet2/Shh-positive RGCs are observed, a phenotype also detected in Zic2 and Foxd1 null embryos. Consistent with this observation, organization of retinal projections at the dorsallateral geniculate nucleus is altered in Boc−/− mice. Analyses of the molecular and cellular consequences of introducing Shh into the developing VTC and Zic2 and Boc into the central retina indicate that Boc expression alone is in sufficient to fully activate the ipsilateral program and that Zic2 regulates Shh expression. Taking these data together, we propose that expression of Boc in cells from the VTC is required to sustain Zic2 expression, likely by regulating the levels of Shh signaling from the nearby cRGCs. Zic2, in turn, directly or indirectly, counteracts Shh and Islet2 expression in the VTC and activates the ipsilateral program.
doi:10.1523/JNEUROSCI.2083-12.2013
PMCID: PMC3827538  PMID: 23678105
3.  Erratum to 
Autophagy  2012;8(7):1163.
doi:10.4161/auto.21428
PMCID: PMC3429560
Lafora disease; autophagy; glycogen metabolism; laforin; malin; neurodegeneration
4.  Shh goes multidirectional in axon guidance 
Cell Research  2011;22(4):611-613.
doi:10.1038/cr.2011.187
PMCID: PMC3317557  PMID: 22105481
5.  The impairment of HCCS leads to MLS syndrome by activating a non-canonical cell death pathway in the brain and eyes 
EMBO Molecular Medicine  2013;5(2):280-293.
Mitochondrial-dependent (intrinsic) programmed cell death (PCD) is an essential homoeostatic mechanism that selects bioenergetically proficient cells suitable for tissue/organ development. However, the link between mitochondrial dysfunction, intrinsic apoptosis and developmental anomalies has not been demonstrated to date. Now we provide the evidence that non-canonical mitochondrial-dependent apoptosis explains the phenotype of microphthalmia with linear skin lesions (MLS), an X-linked developmental disorder caused by mutations in the holo-cytochrome c-type synthase (HCCS) gene. By taking advantage of a medaka model that recapitulates the MLS phenotype we demonstrate that downregulation of hccs, an essential player of the mitochondrial respiratory chain (MRC), causes increased cell death via an apoptosome-independent caspase-9 activation in brain and eyes. We also show that the unconventional activation of caspase-9 occurs in the mitochondria and is triggered by MRC impairment and overproduction of reactive oxygen species (ROS). We thus propose that HCCS plays a key role in central nervous system (CNS) development by modulating a novel non-canonical start-up of cell death and provide the first experimental evidence for a mechanistic link between mitochondrial dysfunction, intrinsic apoptosis and developmental disorders.
doi:10.1002/emmm.201201739
PMCID: PMC3569643  PMID: 23239471
apoptosis; eye development; holo-cytochrome c-type synthase; mitochondrial diseases; MLS syndrome
6.  The Transcription Factor Encyclopedia 
Yusuf, Dimas | Butland, Stefanie L | Swanson, Magdalena I | Bolotin, Eugene | Ticoll, Amy | Cheung, Warren A | Cindy Zhang, Xiao Yu | Dickman, Christopher TD | Fulton, Debra L | Lim, Jonathan S | Schnabl, Jake M | Ramos, Oscar HP | Vasseur-Cognet, Mireille | de Leeuw, Charles N | Simpson, Elizabeth M | Ryffel, Gerhart U | Lam, Eric W-F | Kist, Ralf | Wilson, Miranda SC | Marco-Ferreres, Raquel | Brosens, Jan J | Beccari, Leonardo L | Bovolenta, Paola | Benayoun, Bérénice A | Monteiro, Lara J | Schwenen, Helma DC | Grontved, Lars | Wederell, Elizabeth | Mandrup, Susanne | Veitia, Reiner A | Chakravarthy, Harini | Hoodless, Pamela A | Mancarelli, M Michela | Torbett, Bruce E | Banham, Alison H | Reddy, Sekhar P | Cullum, Rebecca L | Liedtke, Michaela | Tschan, Mario P | Vaz, Michelle | Rizzino, Angie | Zannini, Mariastella | Frietze, Seth | Farnham, Peggy J | Eijkelenboom, Astrid | Brown, Philip J | Laperrière, David | Leprince, Dominique | de Cristofaro, Tiziana | Prince, Kelly L | Putker, Marrit | del Peso, Luis | Camenisch, Gieri | Wenger, Roland H | Mikula, Michal | Rozendaal, Marieke | Mader, Sylvie | Ostrowski, Jerzy | Rhodes, Simon J | Van Rechem, Capucine | Boulay, Gaylor | Olechnowicz, Sam WZ | Breslin, Mary B | Lan, Michael S | Nanan, Kyster K | Wegner, Michael | Hou, Juan | Mullen, Rachel D | Colvin, Stephanie C | Noy, Peter John | Webb, Carol F | Witek, Matthew E | Ferrell, Scott | Daniel, Juliet M | Park, Jason | Waldman, Scott A | Peet, Daniel J | Taggart, Michael | Jayaraman, Padma-Sheela | Karrich, Julien J | Blom, Bianca | Vesuna, Farhad | O'Geen, Henriette | Sun, Yunfu | Gronostajski, Richard M | Woodcroft, Mark W | Hough, Margaret R | Chen, Edwin | Europe-Finner, G Nicholas | Karolczak-Bayatti, Magdalena | Bailey, Jarrod | Hankinson, Oliver | Raman, Venu | LeBrun, David P | Biswal, Shyam | Harvey, Christopher J | DeBruyne, Jason P | Hogenesch, John B | Hevner, Robert F | Héligon, Christophe | Luo, Xin M | Blank, Marissa Cathleen | Millen, Kathleen Joyce | Sharlin, David S | Forrest, Douglas | Dahlman-Wright, Karin | Zhao, Chunyan | Mishima, Yuriko | Sinha, Satrajit | Chakrabarti, Rumela | Portales-Casamar, Elodie | Sladek, Frances M | Bradley, Philip H | Wasserman, Wyeth W
Genome Biology  2012;13(3):R24.
Here we present the Transcription Factor Encyclopedia (TFe), a new web-based compendium of mini review articles on transcription factors (TFs) that is founded on the principles of open access and collaboration. Our consortium of over 100 researchers has collectively contributed over 130 mini review articles on pertinent human, mouse and rat TFs. Notable features of the TFe website include a high-quality PDF generator and web API for programmatic data retrieval. TFe aims to rapidly educate scientists about the TFs they encounter through the delivery of succinct summaries written and vetted by experts in the field. TFe is available at http://www.cisreg.ca/tfe.
doi:10.1186/gb-2012-13-3-r24
PMCID: PMC3439975  PMID: 22458515
7.  Pαx6 Expression in Postmitotic Neurons Mediates the Growth of Axons in Response to SFRP1 
PLoS ONE  2012;7(2):e31590.
During development, the mechanisms that specify neuronal subclasses are coupled to those that determine their axonal response to guidance cues. Pax6 is a homedomain transcription factor required for the specification of a variety of neural precursors. After cell cycle exit, Pax6 expression is often shut down in the precursor progeny and most postmitotic neurons no longer express detectable levels of the protein. There are however exceptions and high Pax6 protein levels are found, for example, in postmitotic retinal ganglion cells (RGCs), dopaminergic neurons of the olfactory bulb and the limbic system in the telencephalon. The function of Pax6 in these differentiating neurons remains mostly elusive. Here, we demonstrate that Pax6 mediates the response of growing axons to SFRP1, a secreted molecule expressed in several Pax6-positive forebrain territories. Forced expression of Pax6 in cultured postmitotic cortical neurons, which do not normally express Pax6, was sufficient to increment axonal length. Growth was blocked by the addition of anti-SFRP1 antibodies, whereas exogenously added SFRP1 increased axonal growth of Pax6-transfected neurons but not that of control or untransfected cortical neurons. In the reverse scenario, shRNA-mediated knock-down of Pax6 in mouse retinal explants specifically abolished RGCs axonal growth induced by SFRP1, but had no effect on RGCs differentiation and it did not modify the effect of Shh or Netrin on axon growth. Taken together these results demonstrate that expression of Pax6 is necessary and sufficient to render postmitotic neurons competent to respond to SFRP1. These results reveal a novel and unexpected function of Pax6 in postmitotic neurons and situate Pax6 and SFRP1 as pair regulators of axonal connectivity.
doi:10.1371/journal.pone.0031590
PMCID: PMC3281087  PMID: 22359602
8.  Cux1 and Cux2 regulate dendritic branching, spine morphology and synapses of the upper layer neurons of the cortex 
Neuron  2010;66(4):523-535.
Summary
Dendrite branching and spine formation determines the function of morphologically distinct and specialized neuronal subclasses. However, little is known about the programs instructing specific branching patterns in vertebrate neurons and whether such programs influence dendritic spines and synapses. Using knockout and knockdown studies combined with morphological, molecular and electrophysiological analysis we show that the homeobox Cux1 and Cux2 are intrinsic and complementary regulators of dendrite branching, spine development and synapse formation in layer II–III neurons of the cerebral cortex. Cux genes control the number and maturation of dendritic spines partly through direct regulation of the expression of Xlr3b and Xlr4b, chromatin remodeling genes previously implicated in cognitive defects. Accordingly, abnormal dendrites and synapses in Cux2−/− mice correlate with reduced synaptic function and defects in working memory. These demonstrate critical roles of Cux in dendritogenesis and highlight novel subclass-specific mechanisms of synapse regulation that contribute to the establishment of cognitive circuits.
doi:10.1016/j.neuron.2010.04.038
PMCID: PMC2894581  PMID: 20510857
cerebral cortex; Cut; Cutl1; Cutl2; transcription factor; dendrite; spine; synapse; synaptogenesis; Xlr
9.  The Netrin-related domain of Sfrp1 interacts with Wnt ligands and antagonizes their activity in the anterior neural plate 
Neural Development  2008;3:19.
Background
Secreted frizzled related proteins (SFRPs) are multifunctional modulators of Wnt and BMP (Bone Morphogenetic Protein) signalling necessary for the development of most organs and the homeostasis of different adult tissues. SFRPs fold in two independent domains: the cysteine rich domain (SfrpCRD) related to the extracellular portion of Frizzled (Fz, Wnt receptors) and the Netrin module (SfrpNTR) defined by homologies with molecules such as Netrin-1, inhibitors of metalloproteinases and complement proteins. Due to its structural relationship with Fz, it is believed that SfrpCRD interferes with Wnt signalling by binding and sequestering the ligand. In contrast, the functional relevance of the SfrpNTR has been barely addressed.
Results
Here, we combine biochemical studies, mutational analysis and functional assays in cell culture and medaka-fish embryos to show that the Sfrp1NTR mimics the function of the entire molecule, binds to Wnt8 and antagonizes Wnt canonical signalling. This activity requires intact tertiary structure and is shared by the distantly related Netrin-1NTR. In contrast, the Sfrp1CRD cannot mirror the function of the entire molecule in vivo but interacts with Fz receptors and antagonizes Wnt8-mediated β-catenin transcriptional activity.
Conclusion
On the basis of these results, we propose that SFRP modulation of Wnt signalling may involve multiple and differential interactions among Wnt, Fz and SFRPs.
doi:10.1186/1749-8104-3-19
PMCID: PMC2542364  PMID: 18715500
10.  Comprehensive characterization of the cis-regulatory code responsible for the spatio-temporal expression of olSix3.2 in the developing medaka forebrain 
Genome Biology  2007;8(7):R137.
A cluster of highly conserved non-coding sequences surrounding the Six3 gene were identified in fish genomes, and transgenesis in medaka fish demonstrates that these sequences have enhancer, silencer and silencer blocker activities that are differentially combined to control the distribution of Six3.
Background
Embryonic development is coordinated by sets of cis-regulatory elements that are collectively responsible for the precise spatio-temporal organization of regulatory gene networks. There is little information on how these elements, which are often associated with highly conserved noncoding sequences, are combined to generate precise gene expression patterns in vertebrates. To address this issue, we have focused on Six3, an important regulator of vertebrate forebrain development.
Results
Using computational analysis and exploiting the diversity of teleost genomes, we identified a cluster of highly conserved noncoding sequences surrounding the Six3 gene. Transgenesis in medaka fish demonstrates that these sequences have enhancer, silencer, and silencer blocker activities that are differentially combined to control the entire distribution of Six3.
Conclusion
This report provides the first example of the precise regulatory code necessary for the expression of a vertebrate gene, and offers a unique framework for defining the interplay of trans-acting factors that control the evolutionary conserved use of Six3.
doi:10.1186/gb-2007-8-7-r137
PMCID: PMC2323233  PMID: 17617896
11.  Meox Homeodomain Proteins Are Required for Bapx1 Expression in the Sclerotome and Activate Its Transcription by Direct Binding to Its Promoter 
Molecular and Cellular Biology  2004;24(7):2757-2766.
The axial skeleton of vertebrates derives from the sclerotomal compartment of the somites. Genetic analysis has demonstrated that the transcription factors Pax1, Pax9, Meox1, Meox2, and Bapx1 are all required for sclerotomal differentiation. Their hierarchical relationship is, however, poorly understood. Because Bapx1 expression in the somites starts slightly later than that of the Meox genes, we asked whether Bapx1 is one of their downstream targets. Our analysis of Meox1; Meox2 mutant mice supports this hypothesis, as Bapx1 expression in the sclerotome is lost in the absence of both Meox proteins. Using transient-transfection assays, we show that Meox1 activates the Bapx1 promoter in a dose-dependent manner and that this activity is enhanced in the presence of Pax1 and/or Pax9. Furthermore, by electrophoretic mobility shift and chromatin immunoprecipitation experiments, we demonstrate that Meox1 can bind the Bapx1 promoter. The palindromic sequence TAATTA, present in the Bapx1 promoter, binds the Meox1 protein in vitro and is necessary for Meox1-induced transactivation of the Bapx1 promoter. Our data demonstrate that the Meox genes are required for Bapx1 expression in the sclerotome and suggest that the mechanism by which the Meox proteins exert this function is through direct activation of the Bapx1 gene.
doi:10.1128/MCB.24.7.2757-2766.2004
PMCID: PMC371113  PMID: 15024065

Results 1-11 (11)