A New Strategy for Constructing Mouse Models of Complex Diseases: Semi-cloning Technology Based on Sperm-like Haploid Embryonic Stem Cells

doi:10.12300/j.issn.1674-5817.2021.143

Abstract

Abstract: The development of haploid genetics has motivated studies on genome evolution and function, especially the technological advancements in recent years have prompted the birth of culture techniques for mammalian haploid embryonic stem cells (haESCs). Sperm-like haESCs are novel haESCs derived from mouse parthenogenetic blastocysts. Sperm-like haESCs only contain paternal genetic material, and their sex chromosome is the X chromosome. They can self-renew, differentiate, and proliferate in vitro for a long time. Furthermore, editing single or multiple genes using the CRISPR system is possible for sperm-like haESCs, which can replace sperms to fertilize oocytes. In contrast to traditional methods for constructing mouse models, such as pronuclear injection, cytoplasmic injection, and tetraploid complementation, by injecting sperm-like haESCs after gene editing into oocytes, semi-cloned mice with a definitive genotype can be obtained efficiently and stably without chimerism, and primary mice can be used for research. The mouse disease model based on multiple precisely edited genes obtained from sperm-like haESCs can explain the effect of multiple genes synergistic interaction at the level of biological individuals to completely simulate various pathological characteristics of complex human diseases that may be affected by multiple genes, and this model facilitates the exploration of novel diagnostic and therapeutic methods.

Key words: Haploid, Sperm-like haploid embryonic stem cells, CRISPR/Cas9, Mouse disease model

CLC Number:

R-332
Q95-33

LAI Suomei,DING Yifu,LI Jinsong. A New Strategy for Constructing Mouse Models of Complex Diseases: Semi-cloning Technology Based on Sperm-like Haploid Embryonic Stem Cells[J]. Laboratory Animal and Comparative Medicine, 2021, 41(5): 369-383. DOI: 10.12300/j.issn.1674-5817.2021.143.

Figures/Tables 4

References

[1] WUTZ A.Haploid animal cells[J]. Development, 2014, 141(7):1423-1426. DOI:10.1242/dev.102202.
[2] HARTWELL L H, CULOTTI J, PRINGLE J R, et al.Genetic control of the cell division cycle in yeast[J]. Science, 1974, 183(4120):46-51. DOI:10.1126/science.183.4120.46.
[3] SHI L, YANG H, LI J.Haploid embryonic stem cells: an ideal tool for mammalian genetic analyses[J]. Protein Cell, 2012, 3(11):806-810. DOI:10.1007/s13238-012-2096-4.
[4] 丁一夫, 李劲松, 周琪. 哺乳动物单倍体胚胎干细胞的建立与应用[J]. 中国科学: 生命科学, 2019, 49(12):1635-1651.
[5] TARKOWSKI A K, ROSSANT J.Haploid mouse blastocysts developed from bisected zygotes[J]. Nature, 1976, 259(5545):663-665. DOI:10.1038/259663a0.
[6] TARKOWSKI A K, WITKOWSKA A, NOWICKA J.Experimental partheonogenesis in the mouse[J]. Nature, 1970, 226(5241):162-165. DOI:10.1038/226162a0.
[7] MODLIŃSKI J A. Haploid mouse embryos obtained by microsurgical removal of one pronucleus[J]. J Embryol Exp Morphol, 1975, 33(4):897-905.
[8] 陈俏羽, 王俊政, 李荣凤. 单倍体胚胎干细胞研究进展及思考[J]. 中国细胞生物学学报, 2017, 39(1):71-77.
[9] LEEB M, WUTZ A.Derivation of haploid embryonic stem cells from mouse embryos[J]. Nature, 2011, 479(7371):131-134. DOI:10.1038/nature10448.
[10] CARETTE J E, GUIMARAES C P, VARADARAJAN M, et al.Haploid genetic screens in human cells identify host factors used by pathogens[J]. Science, 2009, 326(5957):1231-1235. DOI:10.1126/science. 1178955.
[11] CHONG M M, RASMUSSEN J P, RUDENSKY A Y, et al.The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease[J]. J Exp Med, 2008, 205(9):2005-2017. DOI:10.1084/jem. 20081219.
[12] WU H, XU H, MIRAGLIA L J, et al.Human RNase III is a 160-kDa protein involved in preribosomal RNA processing[J]. J Biol Chem, 2000, 275(47):36957-36965. DOI:10.1074/jbc.m005494200.
[13] ELLING U, TAUBENSCHMID J, WIRNSBERGER G, et al.Forward and reverse genetics through derivation of haploid mouse embryonic stem cells[J]. Cell Stem Cell, 2011, 9(6):563-574. DOI:10.1016/j.stem.2011.10.012.
[14] NÜSSLEIN-VOLHARD C, WIESCHAUS E. Mutations affecting segment number and polarity in Drosophila[J]. Nature, 1980, 287(5785):795-801. DOI:10.1038/287795a0.
[15] VANHOOREN V, LIBERT C.The mouse as a model organism in aging research: usefulness, pitfalls and possibilities[J]. Ageing Res Rev, 2013, 12(1):8-21. DOI:10.1016/j.arr.2012.03.010.
[16] IKEHARA Y, YAMAGUCHI T, IKEHARA S.Mouse models of cancer[M]//Glycoscience: Biology and Medicine. Tokyo: Springer Japan, 2014:1-5. DOI:10.1007/978-4-431-54836-2_194-1.
[17] SILVERMAN J L, YANG M, LORD C, et al.Behavioural phenotyping assays for mouse models of autism[J]. Nat Rev Neurosci, 2010, 11(7):490-502. DOI:10.1038/nrn2851.
[18] GOODWILL H L, MANZANO-NIEVES G, GALLO M, et al.Early life stress leads to sex differences in development of depressive-like outcomes in a mouse model[J]. Neuropsychopharmacology, 2019, 44(4):711-720. DOI:10.1038/s41386-018-0195-5.
[19] KEPPLEY L J W, WALKER S J, GADEMSEY A N, et al. Nervonic acid limits weight gain in a mouse model of diet-induced obesity[J]. Faseb J, 2020, 34(11):15314-15326. DOI:10.1096/fj.202000525r.
[20] YANG H, SHI L, WANG B A, et al.Generation of genetically modified mice by oocyte injection of androgenetic haploid embryonic stem cells[J]. Cell, 2012, 149(3):605-617. DOI:10.1016/j.cell.2012.04.002.
[21] WANG L B, LI J S.'Artificial spermatid'-mediated genome editing[J]. Biol Reprod, 2019, 101(3):538-548. DOI:10.1093/biolre/ioz087.
[22] SUBTELNY S.The development of haploid and homozygous diploid frog embryos obtained from transplantations of haploid nuclei[J]. J Exp Zool, 1958, 139(2):263-305. DOI:10.1002/jez.1401390204.
[23] FREED J J, MEZGER-FREED L.Stable haploid cultured cell lines from frog embryos[J]. PNAS, 1970, 65(2):337-344. DOI:10.1073/pnas.65.2.337.
[24] PHILIPPE C, LANDUREAU J C.Culture of cockroach embryonic cells and hemocytes of parthenogenic origin. Maintainance in vitro of haploid and aneuploid forms[J]. Exp Cell Res, 1975, 96(2):287-296. DOI:10.1016/0014-4827(75)90259-1.
[25] DEBEC A.Haploid cell cultures of Drosophila melanogaster[J]. Nature, 1978, 274(5668):255-256. DOI:10.1038/274255a0.
[26] KOTECKI M, REDDY P S, COCHRAN B H.Isolation and characterization of a near-haploid human cell line[J]. Exp Cell Res, 1999, 252(2):273-280. DOI:10.1006/excr.1999.4656.
[27] YI M, HONG N, HONG Y.Generation of medaka fish haploid embryonic stem cells[J]. Science, 2009, 326(5951):430-433. DOI:10.1126/science.1175151.
[28] YING Q L, WRAY J, NICHOLS J, et al.The ground state of embryonic stem cell self-renewal[J]. Nature, 2008, 453(7194):519-523. DOI:10.1038/nature06968.
[29] DAVIES S P, REDDY H, CAIVANO M, et al.Specificity and mechanism of action of some commonly used protein kinase inhibitors[J]. Biochem J, 2000, 351(pt 1):95-105. DOI:10.1042/0264-6021:3510095.
[30] LI W, SHUAI L, WAN H, et al.Androgenetic haploid embryonic stem cells produce live transgenic mice[J]. Nature, 2012, 490(7420):407-411. DOI:10.1038/nature11435.
[31] ZHONG C, YIN Q, XIE Z, et al.CRISPR-Cas9-mediated genetic screening in mice with haploid embryonic stem cells carrying a guide RNA library[J]. Cell Stem Cell, 2015, 17(2):221-232. DOI:10.1016/j.stem.2015.06.005.
[32] YANG H, LIU Z, MA Y, et al.Generation of haploid embryonic stem cells from Macaca fascicularis monkey parthenotes[J]. Cell Res, 2013, 23(10):1187-1200. DOI:10.1038/cr.2013.93.
[33] LI X, CUI X L, WANG J Q, et al.Generation and application of mouse-rat allodiploid embryonic stem cells[J]. Cell, 2016, 164(1-2):279-292. DOI:10.1016/j.cell.2015.11.035.
[34] SAGI I, CHIA G, GOLAN-LEV T, et al.Derivation and differentiation of haploid human embryonic stem cells[J]. Nature, 2016, 532(7597):107-111. DOI:10.1038/nature17408.
[35] ZHONG C, ZHANG M, YIN Q, et al.Generation of human haploid embryonic stem cells from parthenogenetic embryos obtained by microsurgical removal of male pronucleus[J]. Cell Res, 2016, 26(6):743-746. DOI:10.1038/cr.2016.59.
[36] LI Z, WAN H, FENG G, et al.Birth of fertile bimaternal offspring following intracytoplasmic injection of parthenogenetic haploid embryonic stem cells[J]. Cell Res, 2016, 26(1):135-138. DOI:10.1038/cr.2015.151.
[37] LI Z K, WANG L Y, WANG L B, et al. Generation of bimaternal and bipaternal mice from hypomethylated haploid ESCs with imprinting region deletions[J]. Cell Stem Cell, 2018, 23(5):665-676.e4. DOI:10.1016/j.stem.2018.09.004.
[38] JAENISCH R, MINTZ B.Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA[J]. PNAS, 1974, 71(4):1250-1254. DOI:10.1073/pnas.71. 4.1250.
[39] JAENISCH R.Germ line integration and Mendelian transmission of the exogenous Moloney leukemia virus[J]. PNAS, 1976, 73(4):1260-1264. DOI:10.1073/pnas. 73.4.1260.
[40] GORDON J W, SCANGOS G A, PLOTKIN D J, et al.Genetic transformation of mouse embryos by microinjection of purified DNA[J]. PNAS, 1980, 77(12):7380-7384. DOI:10.1073/pnas.77.12.7380.
[41] EVANS M J, KAUFMAN M H.Establishment in culture of pluripotential cells from mouse embryos[J]. Nature, 1981, 292(5819):154-156. DOI:10.1038/292154a0.
[42] SMITHIES O, GREGG R G, BOGGS S S, et al.Insertion of DNA sequences into the human chromosomal β-globin locus by homologous recombination[J]. Nature, 1985, 317(6034):230-234. DOI:10.1038/317230a0.
[43] RAABE T, WESSELSCHMIDT R L. Genetic manipulation of embryonic stem cells[J/OL]. Human Stem Cell Manual, 2007:267-288. https://doi.org/10.1016/B978-012370465-8/50025-9.
[44] THOMAS K R, CAPECCHI M R.Site-directed mutagenesis by gene targeting in mouse embryo-derived stem cells[J]. Cell, 1987, 51(3):503-512. DOI:10.1016/0092-8674(87)90646-5.
[45] GU H, ZOU Y R, RAJEWSKY K.Independent control of immunoglobulin switch recombination at individual switch regions evidenced through Cre-loxP-mediated gene targeting[J]. Cell, 1993, 73(6):1155-1164. DOI:10.1016/0092-8674(93)90644-6.
[46] GEURTS A M, COST G J, FREYVERT Y, et al.Knockout rats via embryo microinjection of zinc-finger nucleases[J]. Science, 2009, 325(5939):433. DOI:10.1126/science.1172447.
[47] MEYER M, DE ANGELIS M H, WURST W, et al. Gene targeting by homologous recombination in mouse zygotes mediated by zinc-finger nucleases[J]. PNAS, 2010, 107(34):15022-15026. DOI:10.1073/pnas. 1009424107.
[48] JINEK M, CHYLINSKI K, FONFARA I, et al.A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity[J]. Science, 2012, 337(6096):816-821. DOI:10.1126/science.1225829.
[49] CONG L, RAN F A, COX D, et al.Multiplex genome engineering using CRISPR/Cas systems[J]. Science, 2013, 339(6121):819-823. DOI:10.1126/science. 231143.
[50] FRASER M J, CARY L, BOONVISUDHI K, et al.Assay for movement of Lepidopteran transposon IFP₂ in insect cells using a baculovirus genome as a target DNA[J]. Virology, 1995, 211(2):397-407. DOI:10.1006/viro.1995.1422.
[51] WILKIE T M, BRINSTER R L, PALMITER R D.Germline and somatic mosaicism in transgenic mice[J]. Dev Biol, 1986, 118(1):9-18. DOI:10.1016/0012-1606(86)90068-0.
[52] WANG H, YANG H, SHIVALILA C S, et al.One-step generation of mice carrying mutations in multiple genes by CRISPR/Cas-mediated genome engineering[J]. Cell, 2013, 153(4):910-918. DOI:10.1016/j.cell. 2013.04.025.
[53] YEN S T, ZHANG M, DENG J M, et al.Somatic mosaicism and allele complexity induced by CRISPR/Cas9 RNA injections in mouse zygotes[J]. Dev Biol, 2014, 393(1):3-9. DOI:10.1016/j.ydbio.2014.06.017.
[54] TARKOWSKI A K.Mouse chimæras developed from fused eggs[J]. Nature, 1961, 190(4779):857-860. DOI:10.1038/190857a0.
[55] GARDNER R L.Mouse chimeras obtained by the injection of cells into the blastocyst[J]. Nature, 1968, 220(5167):596-597. DOI:10.1038/220596a0.
[56] MAHADEVAN M, TSILFIDIS C, SABOURIN L, et al.Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene[J]. Science, 1992, 255(5049):1253-1255. DOI:10.1126/science.1546325.
[57] BROOK J D, MCCURRACH M E, HARLEY H G, et al.Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member[J]. Cell, 1992, 68(4):799-808. DOI:10.1016/0092-8674(92)90154-5.
[58] YIN Q, WANG H, LI N, et al.Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1[J]. Cell Res, 2020, 30(2):133-145. DOI:10.1038/s41422-019-0264-2.
[59] PETTERSSON O J, AAGAARD L, JENSEN T G, et al.Molecular mechanisms in DM1-a focus on foci[J]. Nucleic Acids Res, 2015, 43(4):2433-2441. DOI:10.1093/nar/gkv029.
[60] LEE J E, COOPER T A.Pathogenic mechanisms of myotonic dystrophy[J]. Biochem Soc Trans, 2009, 37(pt 6):1281-1286. DOI:10.1042/bst0371281.
[61] KLESERT T R, CHO D H, CLARK J I, et al.Mice deficient in Six5 develop cataracts: implications for myotonic dystrophy[J]. Nat Genet, 2000, 25(1):105-109. DOI:10.1038/75490.
[62] JANSEN G, GROENEN P J, BÄCHNER D, et al. Abnormal myotonic dystrophy protein kinase levels produce only mild myopathy in mice[J]. Nat Genet, 1996, 13(3):316-324. DOI:10.1038/ng0796-316.
[63] SARKAR P S, APPUKUTTAN B, HAN J, et al.Heterozygous loss of Six5 in mice is sufficient to cause ocular cataracts[J]. Nat Genet, 2000, 25(1):110-114. DOI:10.1038/75500.
[64] MANKODI A, LOGIGIAN E, CALLAHAN L, et al.Myotonic dystrophy in transgenic mice expressing an expanded CUG repeat[J]. Science, 2000, 289(5485):1769-1773. DOI:10.1126/science.289.5485.1769.
[65] GROENEN P, WIERINGA B. Expanding complexity in myotonic dystrophy[J]. Bioessays, 1998, 20(11):901-912. DOI:10.1002/(sici)1521-1878(199811)20:11<901: aid-bies5>3.0.co;2-0.
[66] LARKIN K, FARDAEI M.Myotonic dystrophy: a multigene disorder[J]. Brain Res Bull, 2001, 56(3-4):389-395. DOI:10.1016/s0361-9230(01)00656-6.
[67] VISOOTSAK J, GRAHAM J M.Klinefelter syndrome and other sex chromosomal aneuploidies[J]. Orphanet J Rare Dis, 2006, 1:42. DOI:10.1186/1750-1172-1-42.
[68] RACKOW B W, ARICI A.Reproductive performance of women with müllerian anomalies[J]. Curr Opin Obstet Gynecol, 2007, 19(3):229-237. DOI:10.1097/gco.0b013e32814b0649.
[69] KOBAYASHI A, BEHRINGER R R.Developmental genetics of the female reproductive tract in mammals[J]. Nat Rev Genet, 2003, 4(12):969-980. DOI:10.1038/nrg1225.
[70] WANG L, ZHANG Y, FU X, et al.Joint utilization of genetic analysis and semi-cloning technology reveals a digenic etiology of Müllerian anomalies[J]. Cell Res, 2020, 30(1):91-94. DOI:10.1038/s41422-019-0243-7.
[71] BAI M, HAN Y, WU Y, et al.Targeted genetic screening in mice through haploid embryonic stem cells identifies critical genes in bone development[J]. PLoS Biol, 2019, 17(7): e3000350. DOI:10.1371/journal.pbio.3000350.
[72] LI Q, LI Y, YANG S, et al.CRISPR-Cas9-mediated base-editing screening in mice identifies DND1 amino acids that are critical for primordial germ cell development[J]. Nat Cell Biol, 2018, 20(11):1315-1325. DOI:10.1038/s41556-018-0202-4.
[73] LI Q, LI Y, YANG S, et al.CRISPR-Cas9-mediated base-editing screening in mice identifies DND1 amino acids that are critical for primordial germ cell development[J]. Nat Cell Biol, 2018, 20(11):1315-1325. DOI:10.1038/s41556-018-0202-4.
[74] BADANO J L, KATSANIS N.Beyond Mendel: an evolving view of human genetic disease transmission[J]. Nat Rev Genet, 2002, 3(10):779-789. DOI:10.1038/nrg910.
[75] 吴歆, 耿旭强, 徐沪济. 多基因风险评分在复杂性状疾病中的应用进展[J]. 诊断学理论与实践, 2020, 19(5):540-543. DOI:10.16150/j.1671-2870.2020.05.019.
[76] AL-CHALABI A, HARDIMAN O.The epidemiology of ALS: a conspiracy of genes, environment and time[J]. Nat Rev Neurol, 2013, 9(11):617-628. DOI:10.1038/nrneurol.2013.203.
[77] CHIÒ A, LOGROSCINO G, HARDIMAN O, et al.Prognostic factors in ALS: a critical review[J]. Amyotroph Lateral Scler, 2009, 10(5-6):310-323. DOI:10.3109/17482960802566824.
[78] RAAPHORST J, DE VISSER M, LINSSEN W H, et al.The cognitive profile of amyotrophic lateral sclerosis: a meta-analysis[J]. Amyotroph Lateral Scler, 2010, 11(1-2):27-37. DOI:10.3109/17482960802645008.
[79] CASTELLANOS-MONTIEL M J, CHAINEAU M, DURCAN T M. The neglected genes of ALS: cytoskeletal dynamics impact synaptic degeneration in ALS[J]. Front Cell Neurosci, 2020, 14:594975. DOI:10.3389/fncel.2020.594975.
[80] SELLIER C, CAMPANARI M L, JULIE CORBIER C, et al.Loss of C9ORF72 impairs autophagy and synergizes with polyQ Ataxin-2 to induce motor neuron dysfunction and cell death[J]. EMBO J, 2016, 35(12):1276-1297. DOI:10.15252/embj.201593350.
[81] TAYLOR J P, BROWN R H, CLEVELAND D W.Decoding ALS: from genes to mechanism[J]. Nature, 2016, 539(7628):197-206. DOI:10.1038/nature20413.
[82] GERBINO V, KAUNGA E, YE J, et al. The loss of TBK₁ kinase activity in motor neurons or in all cell types differentially impacts ALS disease progression in SOD1 mice[J]. Neuron, 2020, 106(5):789-805.e5. DOI:10.1016/j.neuron.2020.03.005.
[83] GURNEY M E, PU H, CHIU A Y, et al.Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation[J]. Science, 1994, 264(5166):1772-1775. DOI:10.1126/science.8209258.
[84] CHOU S M, WANG H S, KOMAI K.Colocalization of NOS and SOD1 in neurofilament accumulation within motor neurons of amyotrophic lateral sclerosis: an immunohistochemical study[J]. J Chem Neuroanat, 1996, 10(3-4):249-258. DOI:10.1016/0891-0618(96)00137-8.
[85] BENDOTTI C, TORTAROLO M, SUCHAK S K, et al.Transgenic SOD1 G93A mice develop reduced GLT-1 in spinal cord without alterations in cerebrospinal fluid glutamate levels[J]. J Neurochem, 2001, 79(4):737-746. DOI:10.1046/j.1471-4159.2001.00572.x.
[86] PHILIPS T, ROBBERECHT W.Neuroinflammation in amyotrophic lateral sclerosis: role of glial activation in motor neuron disease[J]. Lancet Neurol, 2011, 10(3):253-263. DOI:10.1016/s1474-4422(11)70015-1.
[87] PHILIPS T, ROTHSTEIN J D. Rodent models of amyotrophic lateral sclerosis[J]. Curr Protoc Pharmacol, 2015, 69:5.67.1-5.67.21. DOI:10.1002/0471141755.ph0567s69.
[88] NIAKAN K K, HAN J N, PEDERSEN R A, et al.Human pre-implantation embryo development[J]. Dev Camb Engl, 2012, 139(5):829-841. DOI:10.1242/dev. 060426.
[89] HASSOLD T, HUNT P.To err (meiotically) is human: the Genesis of human aneuploidy[J]. Nat Rev Genet, 2001, 2(4):280-291. DOI:10.1038/35066065.
[90] GROPP A, WINKING H, HERBST E W, et al.Murine trisomy: developmental profiles of the embryo, and isolation of trisomic cellular systems[J]. J Exp Zool, 1983, 228(2):253-269. DOI:10.1002/jez.1402280210.
[91] BAKER D J, JEGANATHAN K B, CAMERON J D, et al.BubR1 insufficiency causes early onset of aging-associated phenotypes and infertility in mice[J]. Nat Genet, 2004, 36(7):744-749. DOI:10.1038/ng1382.
[92] LAVON N, NARWANI K, GOLAN-LEV T, et al.Derivation of euploid human embryonic stem cells from aneuploid embryos[J]. Stem Cells, 2008, 26(7):1874-1882. DOI:10.1634/stemcells.2008-0156.
[93] BOLTON H, GRAHAM S J L, VAN DER AA N, et al. Mouse model of chromosome mosaicism reveals lineage-specific depletion of aneuploid cells and normal developmental potential[J]. Nat Commun, 2016, 7:11165. DOI:10.1038/ncomms11165.
[94] DAVISSON M T, SCHMIDT C, AKESON E C.Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome[J]. Prog Clin Biol Res, 1990, 360:263-280.
[95] 赵国屏. 从人类基因组计划到精准医学——比较医学的发展趋势与挑战[J]. 实验动物与比较医学, 2021, 41(1):1-8. DOI:10.12300/j.issn.1674-5817.2021.022.