Mouse Tenm4 is required for mesoderm induction

BMC Developmental Biology

Monica J Justice¹  Rita N Cook¹  Hisashi Nakamura¹ 

[1] Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA

关键词: Wnt signaling and ENU mutagenesis;    Bipolar disorder;    Anterior-posterior patterning;    Mesoderm induction;    Gastrulation;    Tenm4;    Mouse;   

Others  :  1085989
DOI  :  10.1186/1471-213X-13-9

 received in 2012-08-23, accepted in 2013-03-19,  发布年份 2013

【 摘 要 】

Background

Tenm4 is a mouse homolog of the Drosophila gene Tenascin-m (Ten-m (Odd oz)), which functions in motor neuron routing. Recently, a genome-wide association analysis for bipolar disorder identified a new susceptibility locus at TENM4 increasing the importance of understanding Tenm4. A series of Tenm4 mouse alleles showing a broad range of phenotypes were isolated after ENU mutagenesis. Here, we examine the timing and features of gastrulation failure in a loss of function allele.

Results

Embryonic mesoderm did not form in loss of function Tenm4^m1/m1 mutant embryos. Genes normally expressed in embryonic mesoderm were not expressed in the mutant, the primitive streak did not form, and markers of the anteroposterior axis were not expressed or were mislocalized. The lack of embryonic mesoderm could not be attributed to poor proliferation of the epiblast, as normal numbers of dividing cells were observed. Epiblast cells maintained expression of Pou5f1 suggesting that they remain pluripotent, but they did not have the capacity to form any germ layer derivatives in teratomas, showing that the inability to induce mesoderm is cell autonomous. Misexpression of E-cadherin and N-cadherin suggest that the embryos did not undergo an epithelial-to-mesenchymal transition. In addition, Wnt signaling did not occur in the mutants, as assessed by the TOPGAL reporter assay, while a GSK3β inhibitor partially rescued the mutant embryos, and rescued TOPGAL reporter expression.

Conclusions

These data demonstrate that Tenm4 mutants fail to form a primitive streak and to induce embryonic mesoderm. Markers of anterior posterior patterning fail to be expressed or are mislocalized. Further, Tenm4 mutants lack the ability to differentiate in a cell autonomous manner. Together, our data suggest that embryos become impaired prior to E6.5 and as a result, Wnt signaling fails to occur; however, the involvement of other signaling pathways remains to be examined.

【 授权许可】

   
2013 Nakamura et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Hogan B, Beddington R, Costantini F, Lacy E: In manipulating the mouse embryo. 2nd edition. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 1994.
• [2]Nagy A, Gertsenstein M, Vintersten K, Behringer R: Manipulating the mouse embryo: a laboratory manual. Cold Spring Harbor, NY: Cold Spring Harbor Laboratory Press; 2002.
• [3]Tam PP, Behringer RR: Mouse gastrulation: the formation of a mammalian body plan. Mech Dev 1997, 68:3-25.
• [4]Marikawa Y: Wnt/beta-catenin signaling and body plan formation in mouse embryos. Semin Cell Dev Biol 2006, 17(2):175-184.
• [5]Liu P, Wakamiya M, Shea MJ, Albrecht U, Behringer RR, Bradley A: Requirement for Wnt3 in vertebrate axis formation. Nat Genet 1999, 22:361-365.
• [6]Conlon FL, Lyons KM, Takaesu N, Barth KS, Kispert A, Herrmann B, Robertson EJ: A primary requirement for nodal in the formation and maintenance of the primitive streak in the mouse. Development 1994, 120:1919-1928.
• [7]Herrmann BG, Kispert A: The T genes in embryogenesis. Trends Genet 1994, 8:280-286.
• [8]Iannaccone PM, Zhou X, Khokha M, Boucher D, Kuehn MR: Insertional mutation of a gene involved in growth regulation of the mouse embryo. Dev Dynamics 1992, 194:198-208.
• [9]Baumgartner S, Martin D, Hagios C, Chiquet-Ehrismann R: Tenm, a Drosophila gene related to tenascin, is a new pair-rule gene. EMBO J 1994, 13:3728-3740.
• [10]Levine A, Bashan-Ahrend A, Budai-Hadrian O, Gartenberg D, Menasherow S, Wides R: Odd Oz: a novel Drosophila pair rule gene. Cell 1994, 77:587-598.
• [11]Tucker RP, Chiquet-Ehrismann R: Teneurins: a conserved family of transmembrane proteins involved in intercellular signaling during development. Dev Biol 2006, 290(2):237-245.
• [12]Zheng L, Michelson Y, Freger V, Avraham Z, Venken KJ, Bellen HJ, Justice MJ, Wides R: Drosophila Ten-m and filamin affect motor neuron growth cone guidance. PLoS One 2011, 6(8):e22956.
• [13]Mosca TJ, Hong W, Dani VS, Favaloro V, Luo L: Trans-synaptic Teneurin signalling in neuromuscular synapse organization and target choice. Nature 2012, 484(7393):237-241.
• [14]Oohashi T, Zhou XH, Feng K, Richter B, Morgelin M, Perez MT, Su WD, Chiquet-Ehrismann R, Rauch U, Fassler R: Mouse ten-m/Odz is a new family of dimeric type II transmembrane proteins expressed in many tissues. J Cell Biol 1999, 145:563-577.
• [15]Wang XZ, Kuroda M, Sok J, Batchvarova N, Kimmel R, Chung P, Zinszner H, Ron D: Identification of novel stress-induced genes downstream of chop. EMBO J 1998, 17:3619-3630.
• [16]Lossie AC, Nakamura H, Thomas SE, Justice MJ: Mutation of l7Rn3 shows that Odz4 is required for mouse gastrulation. Genetics 2005, 169:285-299.
• [17]Zhou XH, Brandau O, Feng K, Oohashi T, Ninomiya Y, Rauch U, Fassler R: The murine Ten-m/Odz genes show distinct but overlapping expression patterns during development and in adult brain. Gene Expr Patterns 2003, 3:397-405.
• [18]Nolan PM, Kapfhamer D, Bucan M: Random mutagenesis screen for dominant behavioral mutations in mice. Methods 1997, 13(4):379-395.
• [19]Rinchik EM, Carpenter DA, Selby PB: A strategy for fine-structure functional analysis of a 6- to 11-centimorgan region of mouse chromosome 7 by high-efficiency mutagenesis. Proc Natl Acad Sci USA 1990, 87:898-900.
• [20]Rinchik EM: Chemical mutagenesis and fine-structure functional analysis of the mouse genome. Trends Genet 1991, 7:15-21.
• [21]Rinchik EM, Carpenter DA: N-ethyl-N-nitrosourea mutagenesis of a 6- to 11-cM subregion of the Fah-Hbb interval of mouse chromosome 7: Completed testing of 4557 gametes and deletion mapping and complementation analysis of 31 mutations. Genetics 1999, 152:373-383.
• [22]Herrmann BG: Expression pattern of the Brachyury gene in whole-mount TWis /TWis mutant embryos. Development 1991, 113:913-917.
• [23]Kispert A, Hermann BG: The Brachyury gene encodes a novel DNA binding protein. EMBO J 1993, 12:3211-3220.
• [24]Blum M, Gaunt SJ, Cho KWY, Steinbeisser H, Blumberg B, Bittner D, De Robertis EM: Gastrulation in the mouse: the homeobox gene goosecoid. Cell 1992, 69:1097-1106.
• [25]Ang SL, Wierda A, Wong D, Stevens KA, Cascio S, Rossant J, Zaret KS: The formation and maintenance of the definitive endoderm lineage in the mouse: involvement of HNF3/forkhead proteins. Development 1993, 119:1301-1315.
• [26]Sasaki H, Hogan BL: Differential expression of multiple fork head related genes during gastrulation and axial pattern formation in the mouse embryo. Development 1993, 118:47-59.
• [27]Barnes JD, Crosby JL, Jones CM, Wright CVE, Hogan BL: Embryonic expression of Lim-1, the mouse homolog of Xenopus Xlim-1, suggests a role in lateral mesoderm differentiation and neurogenesis. Dev Biol 1994, 161:168-178.
• [28]Ang SL, Jin O, Rhinn M, Daigle N, Stevenson L, Rossant J: A targeted mouse Otx2 mutation leads to severe defects in gastrulation and formation of axial mesoderm and to deletion of rostral brain. Development 1996, 122:243-252.
• [29]Winnier G, Blessing M, Labosky PA, Hogan BL: Bone morphogenetic protein-4 is required for mesoderm formation and patterning in the mouse. Genes Dev 1995, 9:2105-2116.
• [30]Solter D, Skreb N, Damjanov I: Extrauterine growth of mouse egg cylinders results in malignant teratoma. Nature 1970, 227:503-504.
• [31]Diwan SB, Stevens LC: Development of teratomas from the ectoderm of mouse egg cylinders. J Natl Cancer Inst 1976, 57:937-942.
• [32]Rosner MH, Vigano MA, Ozato K, Timmons PM, Poirier F, Rigby PW, Staudt LM: A POU-domain transcription factor in early stem cells and germ cells of the mammalian embryo. Nature 1990, 345:686-692.
• [33]Okamoto K, Okazawa H, Okuda A, Sakai M, Muramatsu M, Hamada H: A novel octamer binding transcription factor is differentially expressed in mouse embryonic cells. Cell 1990, 60:461-472.
• [34]Pesce M, Wang X, Wolgemuth DJ, Scholer H: Differential expression of the Oct-4 transcription factor during mouse germ cell differentiation. Mech Dev 1998, 71:89-98.
• [35]Scholer HR, Ruppert S, Suzuki N, Chowdhury K, Gruss P: New type of POU domain in germ line-specific protein Oct-4. Nature 1990, 344:435-439.
• [36]Yeom YI, Fuhrmann G, Ovitt CE, Brehm A, Ohbo K, Gross M, Hubner K, Scholer HR: Germline regulatory element of Oct-4 specific for the totipotent cycle of embryonal cells. Development 1996, 122:881-894.
• [37]DasGupta R, Fuchs E: Multiple roles for activated LEF/TCF transcription complexes during hair follicle development and differentiation. Development 1999, 126:4557-4568.
• [38]Valvezan AJ, Klein PS: GSK-3 and Wnt Signaling in Neurogenesis and Bipolar Disorder. Front Mol Neurosci 2012, 5:1.
• [39]Sato N, Meijer L, Skaltsounis L, Greengard P, Brivanlou AH: Maintenance of pluripotency in human and mouse embryonic stem cells through activation of Wnt signaling by a pharmacological GSK-3-specific inhibitor. Nat Med 2004, 10:55-63.
• [40]Gu Z, Nomura M, Simpson BB, Lei H, Feijen A, van den Eijnden-van Raaji J, Donahoe PK, Li E: The type I activin receptor ActRIB is required for egg cylinder organization and gastrulation in the mouse. Genes Dev 1998, 12:844-857.
• [41]Sirard C, de la Pompa JL, Elia A, Itie A, Mirtsos C, Cheung A, Hahn S, Wakeham A, Schwartz L, Kern SE, Rossant J, Mak TW: The tumor suppressor gene Smad4/Dpc4 is required for gastrulation and later for anterior development of the mouse embryo. Genes Dev 1998, 12:107-119.
• [42]Waldrip WR, Bikoff EK, Hoodless PA, Wrana JL, Robertson EJ: Smad2 signaling in extraembryonic tissues determines anterior-posterior polarity of the early mouse embryo. Cell 1998, 92:797-808.
• [43]Weinstein M, Yang X, Li C, Xu X, Gotay J, Deng CX: Failure of egg cylinder elongation and mesoderm induction in mouse embryos lacking the tumor suppressor smad2. Proc Natl Acad Sci USA 1998, 95:9378-9383.
• [44]James D, Levine AJ, Besser D, Hemmati-Brivanlou A: TGFbeta/activin/nodal signaling is necessary for the maintenance of pluripotency in human embryonic stem cells. Development 2005, 132:1273-1282.
• [45]Chen X, Weisberg E, Fridmacher V, Watanabe M, Naco G, Whitman M: Smad4 and FAST-1 in the assembly of activin-response factor. Nature 1997, 389:85-89.
• [46]Watanabe M, Whitman M: FAST-1 is a key maternal effector of mesoderm inducers in the early Xenopus embryo. Development 1999, 126:5621-5634.
• [47]Mishina Y, Suzuki A, Ueno N, Behringer RR: Bmpr encodes a type I bone morphogenetic protein receptor that is essential for gastrulation during mouse embryogenesis. Genes Dev 1994, 9:3027-3037.
• [48]Coucouvanis E, Martin GR: BMP signaling plays a role in visceral endoderm differentiation and cavitation in the early mouse embryo. Development 1999, 126:535-546.
• [49]Hsieh JC, Lee L, Zhang L, Wefer S, Brown K, DeRossi C, Wines ME, Rosenquist T, Holdener BC: Mesd encodes an LRP5/6 chaperone essential for specification of mouse embryonic polarity. Cell 2003, 112:355-367.
• [50]Kelly OG, Pinson KI, Skarnes WC: The Wnt co-receptors Lrp5 and Lrp6 are essential for gastrulation in mice. Development 2004, 131:2803-2815.
• [51]Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL, Lee JJ, Tilghman SM, Gumbiner BM, Constantini F: The mouse Fused locus encodes Axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 1997, 90:181-192.
• [52]Behrens J, Jerchow BA, Würtele M, Grimm J, Asbrand C, Wirtz R, Kühl M, Wedlich D, Birchmeier W: Functional interaction of an Axin Homolog Conductin, with b-Catenin, APC, and GSK3 b. Science 1998, 280:596-599.
• [53]Moekel M, Huelsken J, Wakamiya M, Ding J, van de Wetering M, Clevers H, Taketo MM, Behringer RR, Shen MM, Birchmeier W: b-catenin regulates Cripto- and Wnt3-dependent gene expression programs in mouse axis and mesoderm formation. Development 2003, 130:6283-6294.
• [54]Huelsken J, Vogel R, Brinkmann V, Erdmann B, Birchmeier C, Birchmeier W: Requirement for beta-catenin in anterior-posterior axis formation in mice. J Cell Biol 2000, 148:567-578.
• [55]Wray J, Hartmann C: WNTing embryonic stem cells. Trends Cell Biol 2012, 22(3):159-168.
• [56]Ciruna B, Rossant J: FGF signaling regulates mesoderm cell fate specification and morphogenetic movement at the primitive streak. Dev Cell 2001, 1:37-49.
• [57]Grimes CA, Jope RS: The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. Prog Neurobiol 2001, 65(4):391-426.
• [58]Clark CE, Nourse CC, Cooper HM: The tangled web of non-canonical Wnt signalling in neural migration. Neurosignals 2012, 20(3):202-220.
• [59]Okerlund ND, Cheyette BN: Synaptic Wnt signaling-a contributor to major psychiatric disorders? J Neurodev Disord 2011, 3(2):162-174.
• [60]Sklar P, Ripke S, Scott LJ, Andreassen OA, Cichon S, Craddock N, Edenberg HJ, Nurnberger JI Jr, Rietschel M, Blackwood D, et al.: Large-scale genome-wide association analysis of bipolar disorder identifies a new susceptibility locus near ODZ4. Nat Genet 2011, 43(10):977-983.
• [61]Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP: Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell 1993, 75:1417-1430.
• [62]Thomas P, Beddington R: Anterior primitive endoderm may be responsible for patterning the anterior neural plate in the mouse embryo. Current biology: CB 1996, 6(11):1487-1496.