Novel insights from fetal and placental phenotyping in 3 mouse models of Down syndrome

Published:March 22, 2021DOI:


      In human fetuses with Down syndrome, placental pathology, structural anomalies and growth restriction are present. There is currently a significant lack of information regarding the early life span in mouse models of Down syndrome.


      The objective of this study was to examine embryonic day 18.5 and placental phenotype in the 3 most common mouse models of Down syndrome (Ts65Dn, Dp(16)1/Yey, Ts1Cje). Based on prenatal and placental phenotyping in 3 mouse models of Down syndrome, we hypothesized that one or more of them would have a similar phenotype to human fetuses with trisomy 21, which would make it the most suitable for in utero treatment studies.

      Study Design

      Here, C57BL6J/6 female mice were mated to Dp(16)1/Yey and Ts1Cje male mice and Ts65Dn female mice to C57BL/B6Eic3Sn.BLiAF1/J male mice. At embryonic day 18.5, dams were euthanized. Embryos and placentas were examined blindly for weight and size. Embryos were characterized as euploid or trisomic, male or female by polymerase chain reaction. A subset of embryos (34 euploid and 34 trisomic) were examined for malformations.


      The Ts65Dn mouse model showed the largest differences in fetal growth, brain development, and placental development when comparing euploid and trisomic embryos. For the Dp(16)1/Yey mouse model, genotype did not impact fetal growth, but there were differences in brain and placental development. For the Ts1Cje mouse model, no significant association was found between genotype and fetal growth, brain development, or placental development. Euploid mouse embryos had no congenital anomalies; however, 1 mouse embryo died. Hepatic necrosis was seen in 6 of 12 Dp(16)1/Yey (50%) and 1 of 12 Ts1Cje (8%) mouse embryos; hepatic congestion or inflammation was observed in 3 of 10 Ts65Dn mouse embryos (30%). Renal pelvis dilation was seen in 5 of 12 Dp(16)1/Yey (42%), 5 of 10 Ts65Dn (50%), and 3 of 12 Ts1Cje (25%) mouse embryos. In addition, 1 Ts65Dn mouse embryo and 1 Dp(16)1/Yey mouse embryo had an aortic outflow abnormality. Furthermore, 2 Ts1Cje mouse embryos had ventricular septal defects. Ts65Dn mouse placentas had increased spongiotrophoblast necrosis.


      Fetal and placental growth showed varying trends across strains. Congenital anomalies were primarily seen in trisomic embryos. The presence of liver abnormalities in all 3 mouse models of Down syndrome (10 of 34 cases) is a novel finding. Renal pelvis dilation was also common (13 of 34 cases). Future research will examine human autopsy material to determine if these findings are relevant to infants with Down syndrome. Differences in placental histology were also observed among strains.

      Key words

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        • de Graaf G.
        • Buckley F.
        • Dever J.
        • Skotko B.G.
        Estimation of live birth and population prevalence of Down syndrome in nine U.S. states.
        Am J Med Genet A. 2017; 173: 2710-2719
        • National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention
        Data and statistics on Down syndrome. Centers for Disease Control and Prevention.
        (Available at:) (Accessed January 10, 2019)
        • Guseh S.H.
        • Little S.E.
        • Bennett K.
        • Silva V.
        • Wilkins-Haug L.E.
        Antepartum management and obstetric outcomes among pregnancies with Down syndrome from diagnosis to delivery.
        Prenat Diagn. 2017; 37: 640-646
        • Sparks T.N.
        • Griffin E.
        • Page J.
        • Pilliod R.
        • Shaffer B.L.
        • Caughey A.B.
        Down syndrome: perinatal mortality risks with each additional week of expectant management.
        Prenat Diagn. 2016; 36: 368-374
        • Wessels M.W.
        • Los F.J.
        • Frohn-Mulder I.M.
        • Niermeijer M.F.
        • Willems P.J.
        • Wladimiroff J.W.
        Poor outcome in Down syndrome fetuses with cardiac anomalies or growth retardation.
        Am J Med Genet A. 2003; 116A: 147-151
        • Aziz N.M.
        • Guedj F.
        • Pennings J.L.A.
        • et al.
        Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome.
        Dis Model Mech. 2018; 11dmm031013
        • Herault Y.
        • Delabar J.M.
        • Fisher E.M.C.
        • Tybulewicz V.L.J.
        • Yu E.
        • Brault V.
        Rodent models in Down syndrome research: impact and future opportunities.
        Dis Model Mech. 2017; 10: 1165-1186
        • Sago H.
        • Carlson E.J.
        • Smith D.J.
        • et al.
        Ts1Cje, a partial trisomy 16 mouse model for Down syndrome, exhibits learning and behavioral abnormalities.
        Proc Natl Acad Sci U S A. 1998; 95: 6256-6261
        • Duchon A.
        • Raveau M.
        • Chevalier C.
        • Nalesso V.
        • Sharp A.J.
        • Herault Y.
        Identification of the translocation breakpoints in the Ts65Dn and Ts1Cje mouse lines: relevance for modeling Down syndrome.
        Mamm Genome. 2011; 22: 674-684
        • Akeson E.C.
        • Lambert J.P.
        • Narayanswami S.
        • Gardiner K.
        • Bechtel L.J.
        • Davisson M.T.
        Ts65Dn -- localization of the translocation breakpoint and trisomic gene content in a mouse model for Down syndrome.
        Cytogenet Cell Genet. 2001; 93: 270-276
        • Davisson M.T.
        • Schmidt C.
        • Akeson E.C.
        Segmental trisomy of murine chromosome 16: a new model system for studying Down syndrome.
        Prog Clin Biol Res. 1990; 360: 263-280
        • Shin M.
        • Siffel C.
        • Correa A.
        Survival of children with mosaic Down syndrome.
        Am J Med Genet A. 2010; 152A: 800-801
        • Li Z.
        • Yu T.
        • Morishima M.
        • et al.
        Duplication of the entire 22.9 mb human chromosome 21 syntenic region on mouse chromosome 16 causes cardiovascular and gastrointestinal abnormalities.
        Hum Mol Genet. 2007; 16: 1359-1366
        • Guedj F.
        • Pennings J.L.
        • Massingham L.J.
        • et al.
        An integrated human/murine transcriptome and pathway approach to identify prenatal treatments for Down syndrome.
        Sci Rep. 2016; 6: 32353
        • Adams A.D.
        • Guedj F.
        • Bianchi D.W.
        Placental development and function in trisomy 21 and mouse models of Down syndrome: clues for studying mechanisms underlying atypical development.
        Placenta. 2020; 89: 58-66
        • Ferrés M.A.
        • Bianchi D.W.
        • Siegel A.E.
        • Bronson R.T.
        • Huggins G.S.
        • Guedj F.
        Perinatal natural history of the Ts1Cje mouse model of Down syndrome: growth restriction, early mortality, heart defects, and delayed development.
        PLoS One. 2016; 11e0168009
        • Olson L.E.
        • Roper R.J.
        • Baxter L.L.
        • Carlson E.J.
        • Epstein C.J.
        • Reeves R.H.
        Down syndrome mouse models Ts65Dn, Ts1Cje, and Ms1Cje/Ts65Dn exhibit variable severity of cerebellar phenotypes.
        Dev Dyn. 2004; 230: 581-589
        • Goodliffe J.W.
        • Olmos-Serrano J.L.
        • Aziz N.M.
        • et al.
        Absence of prenatal forebrain defects in the Dp(16)1Yey/+ mouse model of Down syndrome.
        J Neurosci. 2016; 36: 2926-2944
        • Reinholdt L.G.
        • Ding Y.
        • Gilbert G.J.
        • et al.
        Molecular characterization of the translocation breakpoints in the Down syndrome mouse model Ts65Dn.
        Mamm Genome. 2011; 22: 685-691
        • Salavati N.
        • Smies M.
        • Ganzevoort W.
        • et al.
        The possible role of placental morphometry in the detection of fetal growth restriction.
        Front Physiol. 2018; 9: 1884
        • Salafia C.M.
        • Zhang J.
        • Miller R.K.
        • Charles A.K.
        • Shrout P.
        • Sun W.
        Placental growth patterns affect birth weight for given placental weight.
        Birth Defects Res A Clin Mol Teratol. 2007; 79: 281-288
        • Coan P.M.
        • Angiolini E.
        • Sandovici I.
        • Burton G.J.
        • Constância M.
        • Fowden A.L.
        Adaptations in placental nutrient transfer capacity to meet fetal growth demands depend on placental size in mice.
        J Physiol. 2008; 586: 4567-4576
        • Hayward C.E.
        • Lean S.
        • Sibley C.P.
        • et al.
        Placental adaptation: what can we learn from birthweight:placental weight ratio?.
        Front Physiol. 2016; 7: 28
        • O’Sullivan M.J.
        • Dempsey E.M.
        • Kirwan W.O.
        • Ryan C.A.
        Perinatal hepatic infarction in twin-twin transfusion.
        Prenat Diagn. 2002; 22: 430-432
        • Robbins C.
        • Holzman I.R.
        Diffuse hepatic infarction with complete recovery in a neonate.
        J Pediatr. 1992; 120: 786-788
        • Deodati A.
        • Argemí J.
        • Germani D.
        • et al.
        The exposure to uteroplacental insufficiency is associated with activation of unfolded protein response in postnatal life.
        PLoS One. 2018; 13e0198490
        • Alford K.A.
        • Reinhardt K.
        • Garnett C.
        • et al.
        Analysis of GATA1 mutations in Down syndrome transient myeloproliferative disorder and myeloid leukemia.
        Blood. 2011; 118: 2222-2238
        • Brink D.S.
        Transient leukemia (transient myeloproliferative disorder, transient abnormal myelopoiesis) of Down syndrome.
        Adv Anat Pathol. 2006; 13: 256-262
        • Chen C.P.
        • Lin S.P.
        • Chang T.Y.
        • Ho H.T.
        Abnormal prenatal hematological findings in congenital leukemia of Down syndrome with hepatosplenomegaly.
        Prenat Diagn. 2007; 27: 1266-1267
        • Glasgow A.M.
        • Kapur S.
        • Miller M.K.
        • Brudno S.
        Neonatal hyperammonemia resulting from severe in utero hepatic necrosis.
        J Pediatr. 1986; 108: 136-138
        • Hattori H.
        • Matsuzaki A.
        • Suminoe A.
        • Ihara K.
        • Nakayama H.
        • Hara T.
        High expression of platelet-derived growth factor and transforming growth factor-beta 1 in blast cells from patients with down syndrome suffering from transient myeloproliferative disorder and organ fibrosis.
        Br J Haematol. 2001; 115: 472-475
        • Macones G.A.
        • Johnson A.
        • Tilley D.
        • Wade R.
        • Wapner R.
        Fetal hepatosplenomegaly associated with transient myeloproliferative disorder in trisomy 21.
        Fetal Diagn Ther. 1995; 10: 131-133
        • Ravishankar S.
        • Hoffman L.
        • Lertsburapa T.
        • Welch J.
        • Treaba D.
        • De Paepe M.E.
        Extensive placental choriovascular infiltration by maturing myeloid cells in Down syndrome-associated transient abnormal myelopoiesis.
        Pediatr Dev Pathol. 2015; 18: 231-236
        • Ruchelli E.D.
        • Uri A.
        • Dimmick J.E.
        • et al.
        Severe perinatal liver disease and Down syndrome: an apparent relationship.
        Hum Pathol. 1991; 22: 1274-1280
        • Orzechowski K.M.
        • Berghella V.
        Isolated fetal pyelectasis and the risk of Down syndrome: a meta-analysis.
        Ultrasound Obstet Gynecol. 2013; 42: 615-621
        • Norton M.E.
        Follow-up of sonographically detected soft markers for fetal aneuploidy.
        Semin Perinatol. 2013; 31: 365-369
        • Kupferman J.C.
        • Druschel C.M.
        • Kupchik G.S.
        Increased prevalence of renal and urinary tract anomalies in children with Down syndrome.
        Pediatrics. 2009; 124: e615-e621
        • Stoll C.
        • Dott B.
        • Alembik Y.
        • Roth M.P.
        Associated congenital anomalies among cases with Down syndrome.
        Eur J Med Genet. 2015; 58: 674-680
        • Mercer E.S.
        • Broecker B.
        • Smith E.A.
        • Kirsch A.J.
        • Scherz H.C.
        • A Massad C.
        Urological manifestations of Down syndrome.
        J Urol. 2004; 171: 1250-1253
        • Corteville J.E.
        • Dicke J.M.
        • Crane J.P.
        Fetal pyelectasis and Down syndrome: is genetic amniocentesis warranted?.
        Obstet Gynecol. 1992; 79: 770-772
        • Springer D.A.
        • Allen M.
        • Hoffman V.
        • et al.
        Investigation and identification of etiologies involved in the development of acquired hydronephrosis in aged laboratory mice with the use of high-frequency ultrasound imaging.
        Pathobiol Aging Age Relat Dis. 2014; 4
        • Vis J.C.
        • Duffels M.G.
        • Winter M.M.
        • et al.
        Down syndrome: a cardiovascular perspective.
        J Intellect Disabil Res. 2009; 53: 419-425
        • Antonarakis S.E.
        Down syndrome and the complexity of genome dosage imbalance.
        Nat Rev Genet. 2017; 18: 147-163
        • Li H.
        • Cherry S.
        • Klinedinst D.
        • et al.
        Genetic modifiers predisposing to congenital heart disease in the sensitized Down syndrome population.
        Circ Cardiovasc Genet. 2012; 5: 301-308
        • Lana-Elola E.
        • Watson-Scales S.
        • Slender A.
        • et al.
        Genetic dissection of Down syndrome-associated congenital heart defects using a new mouse mapping panel.
        eLife. 2016; 5: e22614
        • Liu C.
        • Morishima M.
        • Yu T.
        • et al.
        Genetic analysis of Down syndrome-associated heart defects in mice.
        Hum Genet. 2011; 130: 623-632
        • Williams A.D.
        • Mjaatvedt C.H.
        • Moore C.S.
        Characterization of the cardiac phenotype in neonatal Ts65Dn mice.
        Dev Dyn. 2008; 237: 426-435
        • Lorandeau C.G.
        • Hakkinen L.A.
        • Moore C.S.
        Cardiovascular development and survival during gestation in the TS65Dn mouse model for Down syndrome.
        Anat Rec (Hoboken). 2011; 294: 93-101
        • Cross J.C.
        • Hemberger M.
        • Lu Y.
        • et al.
        Trophoblast functions, angiogenesis and remodeling of the maternal vasculature in the placenta.
        Mol Cell Endocrinol. 2002; 17: 202-212
        • Zeng J.
        • Marcus A.
        • Buhtoiarova T.
        • Mittal K.
        Distribution and potential significance of intravillous and intrafibrinous particulate microcalcification.
        Placenta. 2017; 50: 94-98
        • Akirav C.
        • Lu Y.
        • Mu J.
        • et al.
        Ultrasonic detection and developmental changes in calcification of the placenta during normal pregnancy in mice.
        Placenta. 2005; 26: 129-137
        • Diogenes T.C.P.
        • Mourato F.A.
        • de Lima Filho J.L.
        • Mattos S.D.S.
        Gender differences in the prevalence of congenital heart disease in Down’s syndrome: a brief meta-analysis.
        BMC Med Genet. 2017; 18: 111
        • Santoro M.
        • Coi A.
        • Spadoni I.
        • Bianchi F.
        • Pierini A.
        Sex differences for major congenital heart defects in Down syndrome: a population based study.
        Eur J Med Genet. 2018; 61: 546-550
        • Guedj F.
        • Siegel A.E.
        • Pennings J.L.A.
        • et al.
        Apigenin as a candidate prenatal treatment for trisomy 21: Effects in human amniocytes and the Ts1Cje mouse model.
        Am J Hum Genet. 2020; 107: 911-931
        • Blazek J.D.
        • Billingsley C.N.
        • Newbauer A.
        • Roper R.J.
        Embryonic and not maternal trisomy causes developmental attenuation in the Ts65Dn mouse model for Down syndrome.
        Dev Dyn. 2010; 239: 1645-1653
        • Roper R.J.
        • St John H.K.
        • Philip J.
        • Lawler A.
        • Reeves R.H.
        Perinatal loss of Ts65Dn Down syndrome mice.
        Genetics. 2006; 172: 437-443