Animal Reproduction (AR)
Animal Reproduction (AR)

Cell differentiation events in pre-implantation mouse and bovine embryos

Letícia Escobar Carreiro; Gabriel Siqueira dos Santos; Felipe Eduardo Luedke; Marcelo Demarchi Goissis

Downloads: 5
Views: 71


Early mammal embryogenesis starts with oocyte fertilization, giving rise to the zygote. The events that the newly formed zygote surpasses are crucial to the embryo developmental success. Shortly after activation of its genome, cells of the embryo segregate into the inner cell mass (ICM) or the trophectoderm (TE). The first will give rise to the embryo while the latter will become the placenta. This first segregation involves cellular and molecular processes that include cell polarity linked to intracellular pathway activation, which will regulate the transcription of trophectoderm-related genes. Then, cells of the ICM undergo the second event of mammalian cell differentiation, which consists of the separation between epiblast (EPI) and hypoblast or primitive endoderm (PrE). This second segregation involves paracrine signaling, leading to differential expression of key genes that will dictate the fate of the cell. Although these processes are described in detail in the mouse, recent studies suggest that the bovine embryo could also be an interesting model for early development, since there are differences to the mouse and similarities with early human embryogenesis. In this review, we gathered the main data available in the literature upon bovine and mouse early development events, suggesting that both models should be analyzed and studied in a complementary way, to better model early events occurring in human development.


early development, embryogenesis, inner cell mass, trophectoderm, blastocyst


Aberle H, Schwartz H, Kemler R. Cadherin-catenin complex: protein interactions and their implications for cadherin function. J Cell Biochem. 1996;61(4):514-23.<514::AID-JCB4>3.0.CO;2-R. PMid:8806074.

Akizawa H, Nagatomo H, Odagiri H, Kohri N, Yamauchi N, Yanagawa Y, Nagano M, Takahashi M, Kawahara M. Conserved roles of fibroblast growth factor receptor 2 signaling in the regulation of inner cell mass development in bovine blastocysts. Mol Reprod Dev. 2016;83(6):516-25. PMid:27060901.

Alberio R. Regulation of cell fate decisions in early mammalian embryos. Annu Rev Anim Biosci. 2020;8(1):377-93. PMid:31730400.

Anjos SAA, Costa CP, Assumpção MEOA, Visintin JA, Goissis MD. Inhibition of apical domain formation does not block blastocyst development in bovine embryos. Reprod Fertil Dev. 2021;33(10):665. PMid:34092280.

Artus J, Piliszek A, Hadjantonakis AK. The primitive endoderm lineage of the mouse blastocyst: sequential transcription factor activation and regulation of differentiation by Sox17. Dev Biol. 2011;350(2):393-404. PMid:21146513.

Avilion AA, Nicolis SK, Pevny LH, Perez L, Vivian N, Lovell-Badge R. Multipotent cell lineages in early mouse development depend on SOX2 function. Genes Dev. 2003;17(1):126-40. PMid:12514105.

Bassalert C, Valverde-Estrella L, Chazaud C. Primitive endoderm differentiation: from specification to epithelialization. Curr Top Dev Biol. 2018;128:81-104. PMid:29477172.

Beck F, Erler T, Russell A, James R. Expression of Cdx-2 in the mouse embryo and placenta: possible role in patterning of the extra-embryonic membranes. Dev Dyn. 1995;204(3):219-27. PMid:8573715.

Becker DL, Davies CS. Role of gap junctions in the development of the preimplantation mouse embryo. Microsc Res Tech. 1995;31(5):364-74. PMid:8534898.

Berg DK, Smith CS, Pearton DJ, Wells DN, Broadhurst R, Donnison M, Pfeffer PL. Trophectoderm lineage determination in cattle. Dev Cell. 2011;20(2):244-55. PMid:21316591.

Bessonnard S, De Mot L, Gonze D, Barriol M, Dennis C, Goldbeter A, Dupont G, Chazaud C. Gata6, Nanog and Erk signaling control cell fate in the inner cell mass through a tristable regulatory network. Development. 2014;141(19):3637-48. PMid:25209243.

Brown JJ, Whittingham DG. The roles of pyruvate, lactate and glucose during preimplantation development of embryos from F1 hybrid mice in vitro. Development. 1991;112(1):99-105. PMid:1769345.

Canizo JR, Ynsaurralde Rivolta AE, Vazquez Echegaray C, Suvá M, Alberio V, Aller JF, Guberman AS, Salamone DF, Alberio RH, Alberio R. A dose-dependent response to MEK inhibition determines hypoblast fate in bovine embryos. BMC Dev Biol. 2019;19(1):13. PMid:31272387.

Chambers I, Colby D, Robertson M, Nichols J, Lee S, Tweedie S, Smith A. Functional expression cloning of Nanog, a pluripotency sustaining factor in embryonic stem cells. Cell. 2003;113(5):643-55. PMid:12787505.

Chazaud C, Yamanaka Y, Pawson T, Rossant J. Early lineage segregation between epiblast and primitive endoderm in mouse blastocysts through the Grb2-MAPK pathway. Dev Cell. 2006;10(5):615-24. PMid:16678776.

Chen AE, Egli D, Niakan K, Deng J, Akutsu H, Yamaki M, Cowan C, Fitz-Gerald C, Zhang K, Melton DA, Eggan K. Optimal timing of inner cell mass isolation increases the efficiency of human embryonic stem cell derivation and allows generation of sibling cell lines. Cell Stem Cell. 2009a;4(2):103-6. PMid:19200798.

Chen L, Yabuuchi A, Eminli S, Takeuchi A, Lu CW, Hochedlinger K, Daley GQ. Cross-regulation of the Nanog and Cdx2 promoters. Cell Res. 2009b;19(9):1052-61. PMid:19564890.

Chen J, Zhang M. The Par3/Par6/aPKC complex and epithelial cell polarity. Exp Cell Res. 2013;319(10):1357-64. PMid:23535009.

Chi F, Sharpley MS, Nagaraj R, Roy SS, Banerjee U. Glycolysis-independent glucose metabolism distinguishes TE from ICM fate during mammalian embryogenesis. Dev Cell. 2020;53(1):9-26.e4. PMid:32197068.

Cockburn K, Rossant J. Making the blastocyst: lessons from the mouse. J Clin Invest. 2010;120(4):995-1003. PMid:20364097.

Daigneault BW, Rajput S, Smith GW, Ross PJ. Embryonic POU5F1 is required for expanded bovine blastocyst formation. Sci Rep. 2018;8(1):7753. PMid:29773834.

Fleming TP, Johnson MH. From egg to epithelium. Annu Rev Cell Biol. 1988;4(1):459-85. PMid:3058163.

Fleming TP. A quantitative analysis of cell allocation to trophectoderm and inner cell mass in the mouse blastocyst. Dev Biol. 1987;119(2):520-31. PMid:3803716.

Fogarty NME, McCarthy A, Snijders KE, Powell BE, Kubikova N, Blakeley P, Lea R, Elder K, Wamaitha SE, Kim D, Maciulyte V, Kleinjung J, Kim JS, Wells D, Vallier L, Bertero A, Turner JMA, Niakan KK. Genome editing reveals a role for OCT4 in human embryogenesis. Nature. 2017;550(7674):67-73. PMid:28953884.

Frankenberg S, Gerbe F, Bessonnard S, Belville C, Pouchin P, Bardot O, Chazaud C. Primitive endoderm differentiates via a three-step mechanism involving Nanog and RTK signaling. Dev Cell. 2011;21(6):1005-13. PMid:22172669.

Frum T, Watts JL, Ralston A. TEAD4, YAP1 and WWTR1 prevent the premature onset of pluripotency prior to the 16-cell stage. Development. 2019;146(17):dev179861. PMid:31444221.

Fujikura J, Yamato E, Yonemura S, Hosoda K, Masui S, Nakao K, Miyazaki J, Niwa H. Differentiation of embryonic stem cells is induced by GATA factors. Genes Dev. 2002;16(7):784-9. PMid:11937486.

Gardner DK. Changes in requirements and utilization of nutrients during mammalian preimplantation embryo development and their significance in embryo culture. Theriogenology. 1998;49(1):83-102. PMid:10732123.

Gerri C, McCarthy A, Alanis-Lobato G, Demtschenko A, Bruneau A, Loubersac S, Fogarty NME, Hampshire D, Elder K, Snell P, Christie L, David L, van de Velde H, Fouladi-Nashta AA, Niakan KK. Initiation of a conserved trophectoderm program in human, cow and mouse embryos. Nature. 2020;587(7834):443-7. PMid:32968278.

Goissis MD, Cibelli JB. Functional characterization of SOX2 in bovine preimplantation embryos. Biol Reprod. 2014a;90(2):30. PMid:24389873.

Goissis MD, Cibelli JB. Functional characterization of CDX2 during bovine preimplantation development in vitro. Mol Reprod Dev. 2014b;81(10):962-70. PMid:25251051.

Graham CF, Deussen ZA. Features of cell lineage in preimplantation mouse development. J Embryol Exp Morphol. 1978;48(1):53-72. PMid:581769.

Guo G, Huss M, Tong GQ, Wang C, Li Sun L, Clarke ND, Robson P. Resolution of cell fate decisions revealed by single-cell gene expression analysis from zygote to blastocyst. Dev Cell. 2010;18(4):675-85. PMid:20412781.

Harris D, Huang B, Oback B. Inhibition of MAP2K and GSK3 signaling promotes bovine blastocyst development and epiblast-associated expression of pluripotency factors. Biol Reprod. 2013;88(3):74. PMid:23390165.

Johnson MH, McConnell JM. Lineage allocation and cell polarity during mouse embryogenesis. Semin Cell Dev Biol. 2004;15(5):583-97. PMid:15271304.

Johnson MH, Ziomek CA. The foundation of two distinct cell lineages within the mouse morula. Cell. 1981;24(1):71-80. PMid:7237545.

Johnson MH. From mouse egg to mouse embryo: polarities, axes, and tissues. Annu Rev Cell Dev Biol. 2009;25(1):483-512. PMid:19575654.

Johnson MT, Mahmood S, Patel MS. Intermediary metabolism and energetics during murine early embryogenesis. J Biol Chem. 2003;278(34):31457-60. PMid:12788927.

Kaneko KJ, DePamphilis ML. TEAD4 establishes the energy homeostasis essential for blastocoel formation. Development. 2013;140(17):3680-90. PMid:23903192.

Kang M, Piliszek A, Artus J, Hadjantonakis, AK. FGF4 is required for lineage restriction and salt-and-pepper distribution of primitive endoderm factors but not their initial expression in the mouse. Development. 2013;140(2): 267–79. /10.1242/dev.084996. PMid: 23193166.

Keramari M, Razavi J, Ingman KA, Patsch C, Edenhofer F, Ward CM, Kimber SJ. Sox2 is essential for formation of trophectoderm in the preimplantation embryo. PLoS One. 2010;5(11):e13952. PMid:21103067.

Kidder GM, Watson AJ. Roles of Na,K-ATPase in early development and trophectoderm differentiation. Semin Nephrol. 2005;25(5):352-5. PMid:16139691.

Kim SH, Kim MO, Cho YY, Yao K, Kim DJ, Jeong CH, Yu DH, Bae KB, Cho EJ, Jung SK, Lee MH, Chen H, Kim JY, Bode AM, Dong Z. ERK1 phosphorylates Nanog to regulate protein stability and stem cell self-renewal. Stem Cell Res (Amst). 2014;13(1):1-11. PMid:24793005.

Kirchhof N, Carnwath JW, Lemme E, Anastassiadis K, Schöler H, Niemann H. Expression pattern of Oct-4 in preimplantation embryos of different species. Biol Reprod. 2000;63(6):1698-705. PMid:11090438.

Korotkevich E, Niwayama R, Courtois A, Friese S, Berger N, Buchholz F, Hiiragi T. The apical domain is required and sufficient for the first lineage segregation in the mouse embryo. Dev Cell. 2017;40(3):235-247.e7. PMid:28171747.

Kuijk EW, Du Puy L, van Tol HT, Oei CH, Haagsman HP, Colenbrander B, Roelen BA. Differences in early lineage segregation between mammals. Dev Dyn. 2008;237(4):918-27. PMid:18330925.

Kuijk EW, van Tol LTA, Van de Velde H, Wubbolts R, Welling M, Geijsen N, Roelen BAJ. The roles of FGF and MAP kinase signaling in the segregation of the epiblast and hypoblast cell lineages in bovine and human embryos. Development. 2012;139(5):871–82. /10.1242/dev.071688. PMid: 22278923.

Lim HYG, Alvarez YD, Gasnier M, Wang Y, Tetlak P, Bissiere S, Wang H, Biro M, Plachta N. Keratins are asymmetrically inherited fate determinants in the mammalian embryo. Nature. 2020;585(7825):404-9. PMid:32848249.

Lo CW, Gilula NB. Gap junctional communication in the preimplantation mouse embryo. Cell. 1979;18(2):399-409. PMid:498274.

Louvet S, Aghion J, Santa-Maria A, Mangeat P, Maro B. Ezrin becomes restricted to outer cells following asymmetrical division in the preimplantation mouse embryo. Dev Biol. 1996;177(2):568-79. PMid:8806832.

Madeja ZE, Sosnowski J, Hryniewicz K, Warzych E, Pawlak P, Rozwadowska N, Plusa B, Lechniak D. Changes in sub-cellular localization of trophoblast and inner cell mass-specific transcription factors during bovine preimplantation development. BMC Dev Biol. 2013;13(1):32. PMid:23941255.

Maître JL, Turlier H, Illukkumbura R, Eismann B, Niwayama R, Nédélec F, Hiiragi T. Asymmetric division of contractile domains couples cell positioning and fate specification. Nature. 2016;536(7616):344-8. PMid:27487217.

McLean Z, Meng F, Henderson H, Turner P, Oback B. Increased MAP kinase inhibition enhances epiblast-specific gene expression in bovine blastocysts. Biol Reprod. 2014;91(2):49. PMid:25009207.

Misra JR, Irvine KD. The hippo signaling network and its biological functions. Annu Rev Genet. 2018;52(1):65-87. PMid:30183404.

Mitsui K, Tokuzawa Y, Itoh H, Segawa K, Murakami M, Takahashi K, Maruyama M, Maeda M, Yamanaka S. The homeoprotein Nanog is required for maintenance of pluripotency in mouse epiblast and ES cells. Cell. 2003;113(5):631-42. PMid:12787504.

Molotkov A, Mazot P, Brewer JR, Cinalli RM, Soriano P. Distinct Requirements for FGFR1 and FGFR2 in Primitive Endoderm Development and Exit from Pluripotency. Dev Cell. 2017;41(5):511-526.e4. PMid:28552557.

Negrón-Pérez VM, Hansen PJ. Role of yes-associated protein 1, angiomotin, and mitogen-activated kinase kinase 1/2 in development of the bovine blastocyst. Biol Reprod. 2018;98(2):170-83. PMid:29228123.

Niakan KK, Eggan K. Analysis of human embryos from zygote to blastocyst reveals distinct gene expression patterns relative to the mouse. Dev Biol. 2013;375(1):54-64. PMid:23261930.

Nichols J, Zevnik B, Anastassiadis K, Niwa H, Klewe-Nebenius D, Chambers I, Schöler H, Smith A. Formation of pluripotent stem cells in the mammalian embryo depends on the POU transcription factor Oct4. Cell. 1998;95(3):379-91. PMid:9814708.

Nishioka N, Inoue K, Adachi K, Kiyonari H, Ota M, Ralston A, Yabuta N, Hirahara S, Stephenson RO, Ogonuki N, Makita R, Kurihara H, Morin-Kensicki EM, Nojima H, Rossant J, Nakao K, Niwa H, Sasaki H. The Hippo signaling pathway components Lats and Yap pattern Tead4 activity to distinguish mouse trophectoderm from inner cell mass. Dev Cell. 2009;16(3):398-410. PMid:19289085.

Nishioka N, Yamamoto S, Kiyonari H, Sato H, Sawada A, Ota M, Nakao K, Sasaki H. Tead4 is required for specification of trophectoderm in pre-implantation mouse embryos. Mech Dev. 2008;125(3-4):270-83. PMid:18083014.

Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. 2000;24(4):372-6. PMid:10742100.

Niwa H, Toyooka Y, Shimosato D, Strumpf D, Takahashi K, Yagi R, Rossant J. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell. 2005;123(5):917-29. PMid:16325584.

Ortega MS, Kelleher AM, O’Neil E, Benne J, Cecil R, Spencer TE. NANOG is required to form the epiblast and maintain pluripotency in the bovine embryo. Mol Reprod Dev. 2020;87(1):152-60. PMid:31803983.

Ozawa M, Yang QE, Ealy AD. The expression of fibroblast growth factor receptors during early bovine conceptus development and pharmacological analysis of their actions on trophoblast growth in vitro. Reproduction. 2013;145(2):191-201. PMid:23241344.

Pesce M, Schöler HR. Oct-4: gatekeeper in the beginnings of mammalian development. Stem Cells. 2001;19(4):271-8. PMid:11463946.

Plusa B, Frankenberg S, Chalmers A, Hadjantonakis AK, Moore CA, Papalopulu N, Papaioannou VE, Glover DM, Zernicka-Goetz M. Downregulation of Par3 and aPKC function directs cells towards the ICM in the preimplantation mouse embryo. J Cell Sci. 2005;118(Pt 3):505-15. PMid:15657073.

Plusa B, Piliszek A, Frankenberg S, Artus J, Hadjantonakis AK. Distinct sequential cell behaviours direct primitive endoderm formation in the mouse blastocyst. Development. 2008;135(18):3081-91. PMid:18725515.

Posfai E, Petropoulos S, Barros FRO, Schell JP, Jurisica I, Sandberg R, Lanner F, Rossant J. Position- and Hippo signaling-dependent plasticity during lineage segregation in the early mouse embryo. eLife. 2017;6:e22906. PMid:28226240.

Ralston A, Rossant J. Cdx2 acts downstream of cell polarization to cell-autonomously promote trophectoderm fate in the early mouse embryo. Dev Biol. 2008;313(2):614-29. PMid:18067887.

Ralston A, Rossant J. Genetic regulation of stem cell origins in the mouse embryo. Clin Genet. 2005;68(2):106-12. PMid:15996204.

Rossant J, Chazaud C, Yamanaka Y. Lineage allocation and asymmetries in the early mouse embryo. Philos Trans R Soc Lond B Biol Sci. 2003;358(1436):1341-8, discussion 1349. PMid:14511480.

Rossant J. Investigation of the determinative state of the mouse inner cell mass. II. The fate of isolated inner cell masses transferred to the oviduct. J Embryol Exp Morphol. 1975;33(4):991-1001. PMid:1176885.

Ruane PT, Tan CMJ, Adlam DJ, Kimber SJ, Brison DR, Aplin JD, Westwood M. Protein O-GlcNAcylation promotes trophoblast differentiation at implantation. Cells. 2020;9(10):2246. PMid:33036308.

Sakurai N, Takahashi K, Emura N, Hashizume T, Sawai K. Effects of downregulating TEAD4 transcripts by RNA interference on early development of bovine embryos. J Reprod Dev. 2017;63(2):135-42. PMid:27941302.

Schöler HR, Dressler GR, Balling R, Rohdewohld H, Gruss P. Oct-4: a germline-specific transcription factor mapping to the mouse t-complex. EMBO J. 1990;9(7):2185-95. PMid:2357966.

Schrode N, Saiz N, Di Talia S, Hadjantonakis AK. GATA6 levels modulate primitive endoderm cell fate choice and timing in the mouse blastocyst. Dev Cell. 2014;29(4):454-67. PMid:24835466.

Sharma J, Madan P. Characterisation of the Hippo signalling pathway during bovine preimplantation embryo development. Reprod Fertil Dev. 2020;32(4):392-401. PMid:31718770.

Sheng G. Epiblast morphogenesis before gastrulation. Dev Biol. 2015;401(1):17-24. PMid:25446532.

Soszyńska A, Klimczewska K, Suwińska A. FGF/ERK signaling pathway: how it operates in mammalian preimplantation embryos and embryo-derived stem cells. Int J Dev Biol. 2019;63(3-5):171-86. PMid:31058295.

Strumpf D, Mao CA, Yamanaka Y, Ralston A, Chawengsaksophak K, Beck F, Rossant J. Cdx2 is required for correct cell fate specification and differentiation of trophectoderm in the mouse blastocyst. Development. 2005;132(9):2093-102. PMid:15788452.

Tarkowski AK, Wróblewska J. Development of blastomeres of mouse eggs isolated at the 4- and 8-cell stage. J Embryol Exp Morphol. 1967;18(1):155-80. PMid:6048976.

Underhill LA, Robins JC. Trophoblast development in the murine preimplantation embryo. Semin Reprod Med. 2016;34(1):57-62. PMid:26757060.

van Soom A, Boerjan ML, Bols PE, Vanroose G, Lein A, Coryn M, de Kruif A. Timing of compaction and inner cell allocation in bovine embryos produced in vivo after superovulation. Biol Reprod. 1997;57(5):1041-9. PMid:9369168.

van Soom A, van Vlaenderen I, Mahmoudzadeh AR, Deluyker H, de Kruif A. Compaction rate of in vitro fertilized bovine embryos related to the interval from insemination to first cleavage. Theriogenology. 1992;38(5):905-19. PMid:16727189.

Vinot S, Le T, Ohno S, Pawson T, Maro B, Louvet-Vallée S. Asymmetric distribution of PAR proteins in the mouse embryo begins at the 8-cell stage during compaction. Dev Biol. 2005;282(2):307-19. PMid:15950600.

Wang Y, Wang F, Sun T, Trostinskaia A, Wygle D, Puscheck E, Rappolee DA. Entire mitogen activated protein kinase (MAPK) pathway is present in preimplantation mouse embryos. Dev Dyn. 2004;231(1):72-87. PMid:15305288.

Watson AJ, Westhusin ME, De Sousa PA, Betts DH, Barcroft LC. Gene expression regulating blastocyst formation. Theriogenology. 1999;51(1):117-33. PMid:10729067.

Wei Q, Zhong L, Zhang S, Mu H, Xiang J, Yue L, Dai Y, Han J. Bovine lineage specification revealed by single-cell gene expression analysis from zygote to blastocyst. Biol Reprod. 2017;97(1):5-17. PMid:28859285.

White MD, Angiolini JF, Alvarez YD, Kaur G, Zhao ZW, Mocskos E, Bruno L, Bissiere S, Levi V, Plachta N. Long-lived binding of Sox2 to DNA predicts cell fate in the four-cell mouse embryo. Cell. 2016;165(1):75-87. PMid:27015308.

Wicklow E, Blij S, Frum T, Hirate Y, Lang RA, Sasaki H, Ralston A. HIPPO pathway members restrict SOX2 to the inner cell mass where it promotes ICM fates in the mouse blastocyst. PLoS Genet. 2014;10(10):e1004618. PMid:25340657.

Wrenzycki C. Gene expression analysis and in vitro production procedures for bovine preimplantation embryos: past highlights, present concepts and future prospects. Reprod Domest Anim. 2018;53(Suppl 2):14-9. PMid:30238652.

Wu G, Gentile L, Fuchikami T, Sutter J, Psathaki K, Esteves TC, Araúzo-Bravo MJ, Ortmeier C, Verberk G, Abe K, Schöler HR. Initiation of trophectoderm lineage specification in mouse embryos is independent of Cdx2. Development. 2010;137(24):4159-69. PMid:21098565.

Xie D, Chen CC, Ptaszek LM, Xiao S, Cao X, Fang F, Ng HH, Lewin HA, Cowan C, Zhong S. Rewirable gene regulatory networks in the preimplantation embryonic development of three mammalian species. Genome Res. 2010;20(6):804-15. PMid:20219939.

Yagi R, Kohn MJ, Karavanova I, Kaneko KJ, Vullhorst D, DePamphilis ML, Buonanno A. Transcription factor TEAD4 specifies the trophectoderm lineage at the beginning of mammalian development. Development. 2007;134(21):3827-36. PMid:17913785.

Yamanaka Y, Lanner F, Rossant J. FGF signal-dependent segregation of primitive endoderm and epiblast in the mouse blastocyst. Development. 2010;137(5):715-24. PMid:20147376.

Yamanaka Y, Ralston A, Stephenson RO, Rossant J. Cell and molecular regulation of the mouse blastocyst. Dev Dyn. 2006;235(9):2301-14. PMid:16773657.

Yang QE, Fields SD, Zhang K, Ozawa M, Johnson SE, Ealy AD. Fibroblast growth factor 2 promotes primitive endoderm development in bovine blastocyst outgrowths. Biol Reprod. 2011;85(5):946-53. PMid:21778141.

Submitted date:

Accepted date:

61d5e24aa953951ca9485623 animreprod Articles
Links & Downloads

Anim Reprod

Share this page
Page Sections