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Possible Role of Paternal Aberrant Imprinting in Placental Research Article iMedPub Journals Journal of Clinical Epigenetics 2016 http://www.imedpub.com ISSN 2472-1158 Vol. 2 No. 1: 6 DOI: 10.21767/2472-1158.100014 Possible Role of Paternal Aberrant Imprinting Neelam Kedia1,2, Leena Kadam1,3, in Placental Development: A Study in Kushaan Dumasia1 and Tamoxifen Treatment Rat Model Balasinor NH1 1 Neuroendocrinology Division, National Institute for Research in Abstract Reproductive Health, Parel, Mumbai, India Genomic imprinting is known to regulate fetal growth and development. Studies 2 Institute for Stem Cell Biology and from our laboratory have demonstrated that treatment of adult male rats with Regenerative Medicine, National tamoxifen increased post-implantation loss around mid-gestation. Microarray Centre for Biological Sciences, Tata analysis of resorbing vs. normal embryos revealed aberrant expression of Institute of Fundamental Research, imprinted genes and deregulation of genes associated in placental function. GKVK, Bellary Road, Bangalore, India In the present study, expression levels of placental lineage specific genes and 3 Department of Physiology and of imprinted genes implicated in placental development in resorbing embryos sired Obstetrics and Gynaecology, School by tamoxifen treated male rats were evaluated by qPCR. The morphology of of Medicine, Wayne State University, these embryos sired was assessed by routine haematoxylin-eosin staining. Flow cytometry was done to confirm the observed results on increase in trophoblast Detroit, Michigan, USA giant cells. Expression of genes responsible for the formation of trophoblast giant cells, spongiotrophoblast and labyrinth was affected in the resorbing embryos. Morphology of the normal and resorbing embryos sired by tamoxifen treated Corresponding author: Balasinor NH male rats showed increase in giant trophoblast cells along with reduction in spongiotrophoblast and labyrinth trophoblast in the resorbing embryos. The study [email protected] suggests that aberrant imprinting observed upon tamoxifen treatment of adult [email protected] male rats affects placental development by altering the bias towards development of one cell lineage, thus abrogating normal placental structures and highlights role Neuroendocrinology Division, National for paternal imprinting in placentation. Institute for Research in Reproductive Keywords: Placental morphology; Genomic imprinting; Trophoblast giant cells; Health, Parel, Mumbai-400012, India. Embryo loss Abbreviations: ICM: Inner Cell Mass; TE: Trophectoderm; TGC: Trophoblast Giant Tel: +912224192025 Cells; EP: Ectoplacental Cone; TS: Trophoblast Stem Cells; POL: Post Implantation +912224192140 Fax: +912224139412 Loss; CP: Control Normal Placenta; TP: Treated Normal Placenta; CR: Control Resorbing; TR: Treated Resorbing; Cdx2: Caudal Type Homeobox 2; Bhlh: Basic Helix-Loop-Helix; Hand1: Heart and Neural Crest Derivatives Expressed 1; Stra13: Citation: Kedia N, Kadam L, Dumasia K, Stimulated by Retinoic Acid 13; Ascl2: Achaete-Scute Family bHLH Transcription et al. Possible Role of Paternal Aberrant Factor 2; Gcm1: Glial Cells Missing-1; Peg3: Paternally Expressed Gene 3; Dcn: Imprinting in Placental Development: A Decorin; Peg1/Mest: Paternally Expressed Gene 1; Dlk1: Delta-like 1 Homolog; Study in Tamoxifen Treatment Rat Model. J Cdkn1c: Cyclin-Dependent Kinase Inhibitor 1C Clin Epigenet. 2016, 2:1. Received: January 22, 2016; Accepted: February 08, 2016; Published: February 15, 2016 Introduction non-equivalence is genomic imprinting, whereby a subset of genes is expressed from only one specific parental chromosome. Classical nuclear transplantation experiments demonstrated the Most imprinted genes are implicated in growth and development, functional non-equivalence of the two parental pronuclei during and their parental-specific expression is established through embryogenesis and the biasness of paternal genome towards epigenetic modifications in the germ line [2]. the development of extra-embryonic lineages [1]. This functional In mammals, the placenta mediates the exchange of nutrients © Under License of Creative Commons Attribution 3.0 License | This article is available in: http://www.clinical-epigenetics.imedpub.com/ 1 Journal of Clinical Epigenetics 2016 ISSN 2472-1158 Vol. 2 No. 1: 6 between mother and foetus thereby modulating embryo growth. and invasiveness of trophoblast cells [22-24]. Cdkn1c (Cyclin- Placenta formation begins with the segregation of cells of the dependent kinase inhibitor 1C), residing in the Beckwith- morula into the inner cell mass (ICM) and trophectoderm (TE) Wiedmann cluster, is involved in placental development [3]. In rodents, after implantation, the mural trophectoderm [25]. Cdkn1c is involved in G1 cell cycle arrest and has been undergoes differentiation and endoreduplication giving rise to implicated in endoreduplication of TGCs [26]. The Cdkn1c null primary trophoblast giant cells (TGC) which invade the uterus. mice display placentomegaly, with dysplasia of labyrinth and The polar trophectoderm in contact with ICM grows to form the spongiotrophoblast layers [25]. ectoplacental cone (EPC) and the extraembryonic ectoderm, Placental abnormalities account for myriad of developmental both of which contribute to the formation of the placenta. The problems ranging from intrauterine growth retardation to embryo extraembryonic ectoderm develops into the trophoblast cells of loss [27-29]. Our laboratory has been working with tamoxifen, a the chorion layer and gives rise to the labyrinth. The EPC cells selective estrogen receptor modulator in understanding its effect divide to form the spongiotrophoblast which is the compact layer on male fertility. Oral administration of Tamoxifen to adult male of cells sandwiched between the labyrinth and the outer giant cell rats at the dose of 0.4 mg/kg/day for 60 days increases pre- and layer [3]. The cells of the EPC also give rise to secondary TGCs. The post-implantation loss without affecting the fertilizing ability [30, TGC invade into the maternal decidua and are thus important for 31]. This embryo loss correlated with the hypomethylation of anchoring the placenta, whereas the labyrinth layer is the main Igf2-H19 imprint control region (ICR) [32]. Microarray expression site of nutrient exchange. The intermediate spongiotrophoblast studies on the embryos sired by tamoxifen treated rats, revealed layer supports the labyrinth and has been recently implicated to an effect on development, growth, metabolism and differentiation secrete growth factors. Absence and/or defects in either of the 3 associated pathways in the resorbing embryos [33]. Aberrant layers has been associated with placental dysfunction [4, 5]. expression of imprinted genes namely Igf2, Dlk1, Plagl1, Osbpl5, The genes involved in specification and differentiation of these cells Ascl2, Cdkn1c, Phlda2, Igf2r, Grb10, Gpc3, Tbpba and Sgce was types have been elucidated. Cdx2, a homolog of the Drosophila also observed in the resorbing embryos. Down-regulation of homeotic caudal (Cad) gene is involved in the segregation of the cyclins and their dependent kinases and up-regulation of Tgf, ICM and TE lineages and its expression is restricted to the TE [6]. Cdkn1a and Cdkn1b suggested an arrest in cell cycle at the G1- The genes, Hand1 and Stra13 are responsible for differentiation phase in the resorbing embryos [33]. Interestingly, preliminary of TGC and are exclusively expressed only in these cells of the studies on the histology of the resorbing embryos (at embryonic placenta. Over-expression of either Hand1 or Stra13 in TS cell day 20) showed trophoblastic outgrowths [31]. cultures induces differentiation to TGCs [7]. Gcm1 (Glial cells As placental development is crucial for the survival of the embryo, missing-1) controls cell-fate decisions and its expression is in the present study we further characterize the placental defects confined to the labyrinth layer (including syncytiotrophoblast in the resorbing embryos obtained from tamoxifen treated rats at cells) in mouse placenta. Gcm1 knockout mice die around E13. We studied the histology in more detail and also expression embryonic day 10 (E10) due to lack of labyrinth trophoblast of transcripts of placental lineage specific marker genes namely [8, 9] Ascl2 (Mash2), a mammalian member of Achaete-Scute Cdx2, Stra13, Gcm1 and Hand1. We also studied expression family, is essential for spongiotrophoblast formation and imprinted genes namely Peg1, Peg3 and Dcn, known to play a negatively affects TGC differentiation. Ascl2 knockout mice die role in placental function; in the normal and resorbing embryos by E10 due to placental defects, which include the absence of obtained from tamoxifen treated rats at E13. spongiotrophoblast, an increased number of TGCs and a failure in labyrinth formation [10-12]. Materials and Methods Apart from these, a few imprinted genes have been shown to be important for placental development. The paternally expressed Animals and treatment schedule genes, Mest/Peg1, Peg3 both show expression in the trophoblast Randomly bred adult male (75 days old) and female (90 days cells. Peg3 (Paternally expressed gene 3) is expressed by the old) rats of Holtzman strain, maintained at the temperature of cells of spongio- and labyrinth trophoblast and secondary giant 22-23°C, humidity 50-55%, and light: dark cycle of 14:10 h in cells. Peg3 null mice show growth abnormalities and exhibit the Institutes Animal House were used for the study. Food and 25% reduction in placental size [13-15].
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