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Title: The role of PTHrP in murine placental development and function
Author: Duval, Chloe
ISNI:       0000 0004 5355 5712
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2014
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Parathyroid hormone-related peptide (PTHrP) is abundantly expressed throughout the gestational tissues and has multiple roles in fetal development. The importance of PTHrP in embryonic growth and survival is emphasised by the retarded growth and peri-natal lethality of the PTHrP knockout mouse. PTHrP is a regulator of cell survival, proliferation and differentiation in a number of tissues and organs. However, its effects in the development and function of the placenta are yet to be fully defined. Therefore, the PTHrP knockout mouse was used to examine the morphological development and function of the placenta in the absence of fetal PTHrP gene expression. Embryos that were wild-type (WT), heterozygous (HZ) and null (NL) for the PTHrP allele were used for comparison. PTHrP expression was undetectable in the trophoblast cells of the NL placenta, with the HZ placenta exhibiting an intermediate phenotype. Placental development did occur in the absence of fetal PTHrP, although morphological abnormalities were apparent in the junctional zone and labyrinth zone at embryonic day (E)18. The NL placenta was frequently interrupted by large spaces and contained highly misshapen canals, which may reflect altered cellular and cell-matrix interactions. The area of the junctional zone on HZ and NL placental sections was reduced at E14 and E16, as was the area of the labyrinth zone of the NL placenta at E14 and E18. In culture, NL trophoblast cells had a lowered capacity for proliferation and survival. Elevated apoptosis was also observed in the HZ and NL placenta in vivo at E16 and E18, as judged by increased staining for the apoptotic marker, cleaved caspase-3. This effect was less pronounced in the HZ placenta. Evidence of increased insulin-like growth factor 2 (Igf2) expression was observed in the HZ and NL placenta at E14 and E16, which may have been a compensatory response to preserve some aspects of placental function in a PTHrP-deficient environment. Despite a reduced area of junctional and labyrinth zones on NL placental sections, no differences in placental weight was observed at any gestational age examined, which may indicate differences exist in the composition of the NL placenta. Fetal weight was lower in NL than WT fetuses at E16 and E18, whereas fetal weight in the HZ group was unaltered at these gestational ages. This suggests that the NL placenta had a more profoundly reduced capacity to support fetal growth. System A amino acid transport was significantly reduced in the NL placenta at E18, perhaps contributing to decreased NL fetal weight. Glycogen content of the NL placenta was reduced compared to WT at E12 and E14, but raised at E18, which may have been a compensatory mechanism to support fetal growth. In conclusion, PTHrP influences the morphological differentiation of the mouse placenta, trophoblast cell survival, nutrient transport and extraembryonic energy storage. PTHrP is an important regulator of placental development and function, which has associative effects on fetal growth and development.
Supervisor: Kimber, Susan; Glazier, Jocelyn Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: Integrative Mammalian Biology