ESPEYB16 14. Year in Science and Medicine 2019 (1) (18 abstracts)
14.12. Genome amplification and cellular senescence are hallmarks of human placenta development
Velicky P , Meinhardt G , Plessl K , Vondra S , Weiss T , Haslinger P , Lendl T , Aumayr K , Mairhofer M , Zhu X , Schutz B , Hannibal RL , Lindau R , Weil B , Ernerudh J , Neesen J , Egger G , Mikula M , Rohrl C , Urban AE , Baker J , Knofler M & Pollheimer J
Department of Obstetrics and Gynaecology, Reproductive Biology Unit, Medical University of Vienna, Vienna, Austria
To read the full abstract: PLoS Genet 2018;14:e1007698.
These authors studied human placental and decidual tissues obtained from elective pregnancy terminations (6–12 weeks gestation). Placental extravillous trophoblasts (EVTs), the cells that rapidly invade the mother’s endometrium, undergo an initial stage of genomewide amplification leading to a ‘tetraploid’ chromosomal state (XXYY or XXXX) followed by cellular senescence. By contrast, cells from androgenic complete hydatidiform moles (CHM) fail to show normal senescence.
These studies illuminate the marked and rapid cellular changes that occur during early placental formation. Initially, EVTs replicate extensively and rapidly invade the mother’s endometrium, yet the extent of placental invasion is a remarkably well-controlled balance between the fetus’s needs and mother’s self-protection. Here, the authors describe a further genomewide amplification process separate to mitosis and cell division, which leads to ‘tetraploidy’ (2 pairs of chromosomes). The benefit of having an excess of normal chromosome number was not examined, but might allow a brief and extensive burst of gene expression in these highly active cells. Subsequently, on invasion on the endometrium, EVTs quickly undergo growth arrest and cellular senescence, likely as a way to limit the extent of their invasion. By contrast, androgenic hydatidiform moles (cells with diploid chromosomes only from spermatozoa not the ovary) are rare highly aggressive placental tumours – these cells, which lack any DNA of maternal origin, fail to undergo normal cell senescence after invasion.
This crucial balance between the fetus and mother is also upset in some fetal growth disorders. The authors discuss that cases of Beckwith-Wiedemann syndrome characterized by mutations in the cell cycle regulation gene CDNK1C show placental features, such as hyperplasia and excessive EVT formation, that are similar to those seen in hydatidiform moles. It seems likely that more subtle genetic variations in the fetal and maternal genomes may also shift this exquisite balance and explain their separate contributions to variation in birth weight (1).
Reference: 1. Warrington NM, Beaumont RN, Horikoshi M, Day FR, et al. Maternal and fetal genetic effects on birth weight and their relevance to cardio-metabolic risk factors. Nat Genet. 2019 May;51(5):804–814.
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ESPE Yearbook of Paediatric Endocrinology
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