All Title Author
Keywords Abstract

PLOS ONE  2011 

Mediator Subunit 12 Is Required for Neutrophil Development in Zebrafish

DOI: 10.1371/journal.pone.0023845

Full-Text   Cite this paper   Add to My Lib


Hematopoiesis requires the spatiotemporal organization of regulatory factors to successfully orchestrate diverse lineage specificity from stem and progenitor cells. Med12 is a regulatory component of the large Mediator complex that enables contact between the general RNA polymerase II transcriptional machinery and enhancer bound regulatory factors. We have identified a new zebrafish med12 allele, syr, with a single missense mutation causing a valine to aspartic acid change at position 1046. Syr shows defects in hematopoiesis, which predominantly affect the myeloid lineage. Syr has identified a hematopoietic cell-specific requirement for Med12, suggesting a new role for this transcriptional regulator.


[1]  Conaway R, Sato S, Tomomorisato C, Yao T, Conaway J (2005) The mammalian Mediator complex and its role in transcriptional regulation. Trends in Biochemical Sciences 30: 250–255.
[2]  Malik S, Roeder R (2005) Dynamic regulation of pol II transcription by the mammalian Mediator complex. Trends in Biochemical Sciences 30: 256–263.
[3]  Knuesel MT, Meyer KD, Bernecky C, Taatjes DJ (2009) The human CDK8 subcomplex is a molecular switch that controls Mediator coactivator function. Genes Dev 23: 439–451.
[4]  Zhou R, Bonneaud N, Yuan CX, de Santa Barbara P, Boizet B, et al. (2002) SOX9 interacts with a component of the human thyroid hormone receptor-associated protein complex. Nucleic Acids Res 30: 3245–3252.
[5]  Gwack Y, Baek HJ, Nakamura H, Lee SH, Meisterernst M, et al. (2003) Principal Role of TRAP/Mediator and SWI/SNF Complexes in Kaposi's Sarcoma-Associated Herpesvirus RTA-Mediated Lytic Reactivation. Molecular and Cellular Biology 23: 2055–2067.
[6]  Zhou H, Kim S, Ishii S, Boyer TG (2006) Mediator modulates Gli3-dependent Sonic hedgehog signaling. Mol Cell Biol 26: 8667–8682.
[7]  Ding N, Zhou H, Esteve PO, Chin HG, Kim S, et al. (2008) Mediator links epigenetic silencing of neuronal gene expression with x-linked mental retardation. Mol Cell 31: 347–359.
[8]  Taatjes DJ, Marr MT, Tjian R (2004) Regulatory diversity among metazoan co-activator complexes. Nat Rev Mol Cell Biol 5: 403–410.
[9]  Eberhardy SR, Farnham PJ (2002) Myc recruits P-TEFb to mediate the final step in the transcriptional activation of the cad promoter. J Biol Chem 277: 40156–40162.
[10]  Kato Y, Habas R, Katsuyama Y, Naar AM, He X (2002) A component of the ARC/Mediator complex required for TGF beta/Nodal signalling. Nature 418: 641–646.
[11]  Kim S, Xu X, Hecht A, Boyer TG (2006) Mediator is a transducer of Wnt/beta-catenin signaling. J Biol Chem 281: 14066–14075.
[12]  Rocha PP, Scholze M, Bleiss W, Schrewe H (2010) Med12 is essential for early mouse development and for canonical Wnt and Wnt/PCP signaling. Development 137: 2723–2731.
[13]  Hong SK, Haldin CE, Lawson ND, Weinstein BM, Dawid IB, et al. (2005) The zebrafish kohtalo/trap230 gene is required for the development of the brain, neural crest, and pronephric kidney. Proc Natl Acad Sci U S A 102: 18473–18478.
[14]  Rau MJ, Fischer S, Neumann CJ (2006) Zebrafish Trap230/Med12 is required as a coactivator for Sox9-dependent neural crest, cartilage and ear development. Dev Biol 296: 83–93.
[15]  Wang X, Yang N, Uno E, Roeder RG, Guo S (2006) A subunit of the mediator complex regulates vertebrate neuronal development. Proc Natl Acad Sci U S A 103: 17284–17289.
[16]  Shin CH, Chung WS, Hong SK, Ober EA, Verkade H, et al. (2008) Multiple roles for Med12 in vertebrate endoderm development. Dev Biol 317: 467–479.
[17]  Spinks R, Sandhu HK, Andreasen NC, Philibert RA (2004) Association of the HOPA12bp allele with a large X-chromosome haplotype and positive symptom schizophrenia. American Journal of Medical Genetics 127B: 20–27.
[18]  Philibert RA, King BH, Winfield S, Cook EH, Lee YH, et al. (1998) Association of an X-chromosome dodecamer insertional variant allele with mental retardation. Mol Psychiatry 3: 303–309.
[19]  Philibert RA (2006) A meta-analysis of the association of the HOPA12bp polymorphism and schizophrenia. Psychiatr Genet 16: 73–76.
[20]  Lieschke GJ, Oates AC, Paw BH, Thompson MA, Hall NE, et al. (2002) Zebrafish SPI-1 (PU.1) marks a site of myeloid development independent of primitive erythropoiesis: implications for axial patterning. Dev Biol 246: 274–295.
[21]  Thompson MA, Ransom DG, Pratt SJ, MacLennan H, Kieran MW, et al. (1998) The cloche and spadetail genes differentially affect hematopoiesis and vasculogenesis. Dev Biol 197: 248–269.
[22]  Murayama E, Kissa K, Zapata A, Mordelet E, Briolat V, et al. (2006) Tracing hematopoietic precursor migration to successive hematopoietic organs during zebrafish development. Immunity 25: 963–975.
[23]  Crowhurst MO, Layton JE, Lieschke GJ (2002) Developmental biology of zebrafish myeloid cells. Int J Dev Biol 46: 483–492.
[24]  Lieschke GJ, Oates AC, Crowhurst MO, Ward AC, Layton JE (2001) Morphologic and functional characterization of granulocytes and macrophages in embryonic and adult zebrafish. Blood 98: 3087–3096.
[25]  Dale D (2001) Neutropenia and Neutrophilia. In: Beutler E, Lichtman M, Coller B, Kipps T, Seligsohn U, editors. Williams Hematology. New York, Sydney: McGraw-Hill. pp. 823–834.
[26]  Klein C, Grudzien M, Appaswamy G, Germeshausen M, Sandrock I, et al. (2007) HAX1 deficiency causes autosomal recessive severe congenital neutropenia (Kostmann disease). Nat Genet 39: 86–92.
[27]  Dale DC, Person RE, Bolyard AA, Aprikyan AG, Bos C, et al. (2000) Mutations in the gene encoding neutrophil elastase in congenital and cyclic neutropenia. Blood 96: 2317–2322.
[28]  Stumpf M, Waskow C, Krotschel M, van Essen D, Rodriguez P, et al. (2006) The mediator complex functions as a coactivator for GATA-1 in erythropoiesis via subunit Med1/TRAP220. Proc Natl Acad Sci U S A 103: 18504–18509.
[29]  Gobert V, Osman D, Bras S, Auge B, Boube M, et al. (2010) A genome-wide RNA interference screen identifies a differential role of the mediator CDK8 module subunits for GATA/RUNX-activated transcription in Drosophila. Mol Cell Biol 30: 2837–2848.
[30]  Su AI, Cooke MP, Ching KA, Hakak Y, Walker JR, et al. (2002) Large-scale analysis of the human and mouse transcriptomes. Proc Natl Acad Sci U S A 99: 4465–4470.
[31]  Taussig MJ, Stoevesandt O, Borrebaeck CA, Bradbury AR, Cahill D, et al. (2007) ProteomeBinders: planning a European resource of affinity reagents for analysis of the human proteome. Nat Methods 4: 13–17.
[32]  Hoffman B, Liebermann DA, Selvakumaran M, Nguyen HQ (1996) Role of c-myc in myeloid differentiation, growth arrest and apoptosis. Curr Top Microbiol Immunol 211: 17–27.
[33]  O'Neil J, Look AT (2007) Mechanisms of transcription factor deregulation in lymphoid cell transformation. Oncogene 26: 6838–6849.
[34]  Meijer AH, van der Sar AM, Cunha C, Lamers GE, Laplante MA, et al. (2008) Identification and real-time imaging of a myc-expressing neutrophil population involved in inflammation and mycobacterial granuloma formation in zebrafish. Dev Comp Immunol 32: 36–49.
[35]  Liu X, Vorontchikhina M, Wang YL, Faiola F, Martinez E (2008) STAGA recruits Mediator to the MYC oncoprotein to stimulate transcription and cell proliferation. Mol Cell Biol 28: 108–121.
[36]  Craven SE, French D, Ye W, de Sauvage F, Rosenthal A (2005) Loss of Hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndrome. Blood 105: 3528–3534.
[37]  Uechi T, Nakajima Y, Chakraborty A, Torihara H, Higa S, et al. (2008) Deficiency of ribosomal protein S19 during early embryogenesis leads to reduction of erythrocytes in a zebrafish model of Diamond-Blackfan anemia. Hum Mol Genet 17: 3204–3211.
[38]  Bai X, Kim J, Yang Z, Jurynec MJ, Akie TE, et al. (2010) TIF1gamma controls erythroid cell fate by regulating transcription elongation. Cell 142: 133–143.
[39]  Bolli N, Payne EM, Rhodes J, Gjini E, Johnston AB, et al. (2011) cpsf1 is required for definitive hematopoietic stem cell survival in zebrafish. Blood.
[40]  Taatjes DJ (2010) The human Mediator complex: a versatile, genome-wide regulator of transcription. Trends Biochem Sci 35: 315–322.
[41]  Kagey MH, Newman JJ, Bilodeau S, Zhan Y, Orlando DA, et al. (2010) Mediator and cohesin connect gene expression and chromatin architecture. Nature 467: 430–435.
[42]  Hogan BM, Layton JE, Pyati UJ, Nutt SL, Hayman JW, et al. (2006) Specification of the Primitive Myeloid Precursor Pool Requires Signaling through Alk8 in Zebrafish. Current Biology 16: 506–511.
[43]  Lawson ND, Weinstein BM (2002) In vivo imaging of embryonic vascular development using transgenic zebrafish. Dev Biol 248: 307–318.
[44]  Renshaw SA, Loynes CA, Trushell DM, Elworthy S, Ingham PW, et al. (2006) A transgenic zebrafish model of neutrophilic inflammation. Blood 108: 3976–3978.


comments powered by Disqus