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Cited by 13Developmental Biology and Gene RegulationGenomics and Chromatin DynamicsCongenital limb and hand anomalies

Targeted Deletion of Btg1 and Btg2 Results in Homeotic Transformation of the Axial Skeleton

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Tijchon, Esther, van Ingen Schenau, Dorette, van Opzeeland, Fred, Tirone, Felice, Hoogerbrugge, Peter M., Van Leeuwen, Frank N., Scheijen, Blanca·2015·PLOS ONE
DOI 10.1371/journal.pone.0131481PMC PMC4517811
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Abstract

Btg1 and Btg2 encode highly homologous proteins that are broadly expressed in different cell lineages, and have been implicated in different types of cancer. Btg1 and Btg2 have been shown to modulate the function of different transcriptional regulators, including Hox and Smad transcription factors. In this study, we examined the in vivo role of the mouse Btg1 and Btg2 genes in specifying the regional identity of the axial skeleton. Therefore, we examined the phenotype of Btg1 and Btg2 single knockout mice, as well as novel generated Btg1-/-;Btg2-/- double knockout mice, which were viable, but displayed a non-mendelian inheritance and smaller litter size. We observed both unique and overlapping phenotypes reminiscent of homeotic transformation along the anterior-posterior axis in the single and combined Btg1 and Btg2 knockout animals. Both Btg1-/- and Btg2-/- mice displayed partial posterior transformation of the seventh cervical vertebra, which was more pronounced in Btg1-/-;Btg2-/- mice, demonstrating that Btg1 and Btg2 act in synergy. Loss of Btg2, but not Btg1, was sufficient for complete posterior transformation of the thirteenth thoracic vertebra to the first lumbar vertebra. Moreover, Btg2-/- animals displayed complete posterior transformation of the sixth lumbar vertebra to the first sacral vertebra, which was only partially present at a low frequency in Btg1-/- mice. The Btg1-/-;Btg2-/- animals showed an even stronger phenotype, with L5 to S1 transformation. Together, these data show that both Btg1 and Btg2 are required for normal vertebral patterning of the axial skeleton, but each gene contributes differently in specifying the identity along the anterior-posterior axis of the skeleton.

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  • The miR-140-5p-G targets include many genes important for skeletal development and homeostasis, including Loxl3, Btg1, and Trps1, and genes associated with various metabolic pathways.

    “The miR-140-5p-G targets include many genes important for skeletal development and homeostasis, including Loxl3, Btg1, and Trps1, and genes associated with various metabolic pathways”

    From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [23]

    The Discussion (page not available in our copy) says Btg1 and Btg2 play an important role in vertebral patterning, supporting Btg1’s relevance to skeletal development. The paper does not establish that Btg1, Loxl3, or Trps1 are miR-140-5p-G targets, or address the claimed metabolic-pathway targets. (LLM, conf=0.88)

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  1. [1]Dubrulle J, Pourquie O. Coupling segmentation to axis formation. Development. 2004; 131(23): 5783– 93. Epub 2004/11/13. 15539483
  2. [2]Hirsinger E, Jouve C, Dubrulle J, Pourquie O. Somite formation and patterning. International review of cytology. 2000; 198: 1– 65. Epub 2000/05/11. 10804460
  3. [3]Krumlauf R. Hox genes in vertebrate development. Cell. 1994; 78(2): 191– 201. Epub 1994/07/29. 7913880
  4. [4]Duboule D. The rise and fall of Hox gene clusters. Development. 2007; 134(14): 2549– 60. Epub 2007/06/08. 17553908
  5. [5]Duboule D, Dolle P. The structural and functional organization of the murine HOX gene family resembles that of Drosophila homeotic genes. The EMBO journal. 1989; 8(5): 1497– 505. Epub 1989/05/01. 2569969 PMC400980
  6. [6]Graham A, Papalopulu N, Krumlauf R. The murine and Drosophila homeobox gene complexes have common features of organization and expression. Cell. 1989; 57(3): 367– 78. Epub 1989/05/05. 2566383
  7. [7]Alexander T, Nolte C, Krumlauf R. Hox genes and segmentation of the hindbrain and axial skeleton. Annual review of cell and developmental biology. 2009; 25: 431– 56. Epub 2009/07/07. 10.1146/annurev.cellbio.042308.113423 19575673 · DOI
  8. [8]Mallo M, Wellik DM, Deschamps J. Hox genes and regional patterning of the vertebrate body plan. Developmental biology. 2010; 344(1): 7– 15. Epub 2010/05/04. 10.1016/j.ydbio.2010.04.024 20435029 PMC2909379 · DOI
  9. [9]Tschopp P, Duboule D. A genetic approach to the transcriptional regulation of Hox gene clusters. Annual review of genetics. 2011; 45: 145– 66. Epub 2011/11/09. 10.1146/annurev-genet-102209-163429 22060042 · DOI
  10. [10]Cernilogar FM, Orlando V. Epigenome programming by Polycomb and Trithorax proteins. Biochemistry and cell biology = Biochimie et biologie cellulaire. 2005; 83(3): 322– 31. Epub 2005/06/17. 15959558
  11. [11]Grimaud C, Negre N, Cavalli G. From genetics to epigenetics: the tale of Polycomb group and trithorax group genes. Chromosome research: an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology. 2006; 14(4): 363– 75. Epub 2006/07/06. 16821133
  12. [12]Mallo M, Vinagre T, Carapuco M. The road to the vertebral formula. The International journal of developmental biology. 2009; 53(8–10): 1469– 81. Epub 2009/02/28. 10.1387/ijdb.072276mm 19247958 · DOI
  13. [13]Benazeraf B, Pourquie O. Formation and segmentation of the vertebrate body axis. Annual review of cell and developmental biology. 2013; 29: 1– 26. Epub 2013/07/03. 10.1146/annurev-cellbio-101011-155703 23808844 · DOI
  14. [14]Rouault JP, Falette N, Guehenneux F, Guillot C, Rimokh R, Wang Q, et al Identification of BTG2, an antiproliferative p53-dependent component of the DNA damage cellular response pathway. Nature genetics. 1996; 14(4): 482– 6. Epub 1996/12/01. 8944033
  15. [15]Winkler GS. The mammalian anti-proliferative BTG/Tob protein family. Journal of cellular physiology. 2010; 222(1): 66– 72. Epub 2009/09/12. 10.1002/jcp.21919 19746446 · DOI
  16. [16]Sun Q, Hang M, Guo X, Shao W, Zeng G. Expression and significance of miRNA-21 and BTG2 in lung cancer. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine. 2013; 34(6): 4017– 26. Epub 2013/07/17. 23857284
  17. [17]Zhao Y, Gou WF, Chen S, Takano Y, Xiu YL, Zheng HC. BTG1 expression correlates with the pathogenesis and progression of ovarian carcinomas. International journal of molecular sciences. 2013; 14(10): 19670– 80. Epub 2013/10/03. 10.3390/ijms141019670 24084718 PMC3821579 · DOI
  18. [18]Kuiper RP, Schoenmakers EF, van Reijmersdal SV, Hehir-Kwa JY, van Kessel AG, van Leeuwen FN, et al High-resolution genomic profiling of childhood ALL reveals novel recurrent genetic lesions affecting pathways involved in lymphocyte differentiation and cell cycle progression. Leukemia. 2007; 21(6): 1258– 66. Epub 2007/04/20. 17443227
  19. [19]Sheng SH, Zhao CM, Sun GG. BTG1 expression correlates with the pathogenesis and progression of breast carcinomas. Tumour biology: the journal of the International Society for Oncodevelopmental Biology and Medicine. 2014; 35(4): 3317– 26. Epub 2013/11/26. 24272202
  20. [20]Mullighan CG, Goorha S, Radtke I, Miller CB, Coustan-Smith E, Dalton JD, et al Genome-wide analysis of genetic alterations in acute lymphoblastic leukaemia. Nature. 2007; 446(7137): 758– 64. Epub 2007/03/09. 17344859
  21. [21]Lohr JG, Stojanov P, Lawrence MS, Auclair D, Chapuy B, Sougnez C, et al Discovery and prioritization of somatic mutations in diffuse large B-cell lymphoma (DLBCL) by whole-exome sequencing. Proceedings of the National Academy of Sciences of the United States of America. 2012; 109(10): 3879– 84. Epub 2012/02/22. 10.1073/pnas.1121343109 22343534 PMC3309757 · DOI
  22. [22]Morin RD, Mendez-Lago M, Mungall AJ, Goya R, Mungall KL, Corbett RD, et al Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma. Nature. 2011; 476(7360): 298– 303. Epub 2011/07/29. 10.1038/nature10351 21796119 PMC3210554 · DOI · Paper page
  23. [23]Park S, Lee YJ, Lee HJ, Seki T, Hong KH, Park J, et al B-cell translocation gene 2 (Btg2) regulates vertebral patterning by modulating bone morphogenetic protein/smad signaling. Molecular and cellular biology. 2004; 24(23): 10256– 62. Epub 2004/11/16. 15542835 PMC529031
  24. [24]Prevot D, Voeltzel T, Birot AM, Morel AP, Rostan MC, Magaud JP, et al The leukemia-associated protein Btg1 and the p53-regulated protein Btg2 interact with the homeoprotein Hoxb9 and enhance its transcriptional activation. The Journal of biological chemistry. 2000; 275(1): 147– 53. Epub 2000/01/05. 10617598
  25. [25]Alharbi RA, Pettengell R, Pandha HS, Morgan R. The role of HOX genes in normal hematopoiesis and acute leukemia. Leukemia. 2013; 27(5): 1000– 8. Epub 2012/12/06. 10.1038/leu.2012.356 23212154 · DOI
  26. [26]Radulovic V, de Haan G, Klauke K. Polycomb-group proteins in hematopoietic stem cell regulation and hematopoietic neoplasms. Leukemia. 2013; 27(3): 523– 33. Epub 2012/12/22. 10.1038/leu.2012.368 23257781 · DOI
  27. [27]Casaca A, Santos AC, Mallo M. Controlling Hox gene expression and activity to build the vertebrate axial skeleton. Developmental dynamics: an official publication of the American Association of Anatomists. 2014; 243(1): 24– 36. Epub 2013/07/03. 23813547
  28. [28]Farioli-Vecchioli S, Micheli L, Saraulli D, Ceccarelli M, Cannas S, Scardigli R, et al Btg1 is Required to Maintain the Pool of Stem and Progenitor Cells of the Dentate Gyrus and Subventricular Zone. Frontiers in neuroscience. 2012; 6: 124 Epub 2012/09/13. 10.3389/fnins.2012.00124 22969701 PMC3431174 · DOI
  29. [29]Horan GS, Wu K, Wolgemuth DJ, Behringer RR. Homeotic transformation of cervical vertebrae in Hoxa-4 mutant mice. Proceedings of the National Academy of Sciences of the United States of America. 1994; 91(26): 12644– 8. Epub 1994/12/20. 7809093 PMC45495
  30. [30]Ding M, Lu Y, Abbassi S, Li F, Li X, Song Y, et al Targeting Runx2 expression in hypertrophic chondrocytes impairs endochondral ossification during early skeletal development. Journal of cellular physiology. 2012; 227(10): 3446– 56. Epub 2012/01/10. 10.1002/jcp.24045 22223437 PMC3359397 · DOI
  31. [31]Soung do Y, Talebian L, Matheny CJ, Guzzo R, Speck ME, Lieberman JR, et al Runx1 dose-dependently regulates endochondral ossification during skeletal development and fracture healing. Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research. 2012; 27(7): 1585– 97. Epub 2012/03/21. PMC3377839 22431360
  32. [32]van der Lugt NM, Domen J, Linders K, van Roon M, Robanus-Maandag E, te Riele H, et al Posterior transformation, neurological abnormalities, and severe hematopoietic defects in mice with a targeted deletion of the bmi-1 proto-oncogene. Genes & development. 1994; 8(7): 757– 69. Epub 1994/04/01. 7926765
  33. [33]Core N, Bel S, Gaunt SJ, Aurrand-Lions M, Pearce J, Fisher A, et al Altered cellular proliferation and mesoderm patterning in Polycomb-M33-deficient mice. Development. 1997; 124(3): 721– 9. Epub 1997/02/01. 9043087
  34. [34]Akasaka T, van Lohuizen M, van der Lugt N, Mizutani-Koseki Y, Kanno M, Taniguchi M, et al Mice doubly deficient for the Polycomb Group genes Mel18 and Bmi1 reveal synergy and requirement for maintenance but not initiation of Hox gene expression. Development. 2001; 128(9): 1587– 97. Epub 2001/04/06. 11290297
  35. [35]Bel S, Core N, Djabali M, Kieboom K, Van der Lugt N, Alkema MJ, et al Genetic interactions and dosage effects of Polycomb group genes in mice. Development. 1998; 125(18): 3543– 51. Epub 1998/08/26. 9716520
  36. [36]Storre J, Elsasser HP, Fuchs M, Ullmann D, Livingston DM, Gaubatz S. Homeotic transformations of the axial skeleton that accompany a targeted deletion of E2f6. EMBO reports. 2002; 3(7): 695– 700. Epub 2002/07/09. 12101104 PMC1084195
  37. [37]Attwooll C, Lazzerini Denchi E, Helin K. The E2F family: specific functions and overlapping interests. The EMBO journal. 2004; 23(24): 4709– 16. Epub 2004/11/13. 15538380 PMC535093
  38. [38]Trimarchi JM, Fairchild B, Wen J, Lees JA. The E2F6 transcription factor is a component of the mammalian Bmi1-containing polycomb complex. Proceedings of the National Academy of Sciences of the United States of America. 2001; 98(4): 1519– 24. Epub 2001/02/15. 11171983 PMC29289
  39. [39]Isono K, Mizutani-Koseki Y, Komori T, Schmidt-Zachmann MS, Koseki H. Mammalian polycomb-mediated repression of Hox genes requires the essential spliceosomal protein Sf3b1. Genes & development. 2005; 19(5): 536– 41. Epub 2005/03/03. 15741318 PMC551574
  40. [40]Ogawa H, Ishiguro K, Gaubatz S, Livingston DM, Nakatani Y. A complex with chromatin modifiers that occupies E2F- and Myc-responsive genes in G0 cells. Science. 2002; 296(5570): 1132– 6. Epub 2002/05/11. 12004135
  41. [41]Courel M, Friesenhahn L, Lees JA. E2f6 and Bmi1 cooperate in axial skeletal development. Developmental dynamics: an official publication of the American Association of Anatomists. 2008; 237(5): 1232– 42. Epub 2008/03/28. 18366140 PMC2697036

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Authors
Tijchon, E., van Ingen Schenau, D., van Opzeeland, F., Tirone, F., Hoogerbrugge, P. M., Van Leeuwen, F. N., & Scheijen, B.
Affiliations
  • Radboud University Medical Center (NL)
  • Fondazione Santa Lucia (IT)
  • Princess Máxima Center (NL)
Corresponding author
Scheijen, Blanca
ORCID
Venue
PLOS ONE
Publisher
Public Library of Science (PLoS)
Published
2015-07-28
Volume
10
Issue
7
Pages
e0131481
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0131481
PMC
PMC4517811
OpenAlex
W1502433641
Cited by
13
References
0
Citations by year
2026: 1 · 2025: 1 · 2023: 1 · 2022: 1 · 2021: 1 · 2019: 2 · 2018: 2 · 2016: 2 · 2015: 2
FWCI
0.87
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Radboud Repository (Radboud University) (submittedVersion, other-oa)
Funders
Stichting Kinderen Kankervrij
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
Keywords
BTG1, BTG2, homeotic transformation, axial skeleton, anterior-posterior axis, cervical vertebrae, thoracic vertebrae, lumbar vertebrae, sacral vertebrae, double knockout mice, non-Mendelian inheritance, gene dosage, Hox transcription factors, Smad transcription factors
MeSH terms
Animals, Neoplasm Proteins, Phenotype, Spine, Immediate-Early Proteins, Mice, Knockout, Tumor Suppressor Proteins, Mice

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