Investigating the Role of Protoporphyrinogen oxidase (Ppox) during Murine Embryonic Development

Presenter

Emily Pease

Campus

UMass Amherst

Sponsor

Kimberly D. Tremblay, Department of Animal Sciences, UMass Amherst

Schedule

Session 4, 2:30 PM - 3:15 PM [Schedule by Time][Poster Grid for Time/Location]

Location

Poster Board A36, Campus Center Auditorium, Row 2 (A21-A40) [Poster Location Map]

Abstract

Protoporphyrinogen oxidase (Ppox) is the penultimate enzyme in the heme biosynthesis pathway. Autosomal dominant loss-of-function Ppox mutations in humans cause a rare metabolic disorder called variegate porphyria, of which the cellular and systematic biology of porphyrias are poorly understood and have rarely been studied in a developmental context. To address knowledge gaps in the roles of Ppox and heme during mammalian development, a Ppox -/- mouse model was generated and screened for embryonic lethality in collaboration with the Knockout Mouse Phenotyping (KOMP) program. Analysis of Ppox null embryos reveals developmental delay beyond embryonic day 7.5 (E7.5), and failure to complete chorioallantoic fusion and initiate placentation by E9.0. Without a connection to the placenta, these null embryos precipitously decline and exhibit lethality by E10.5. In situ hybridization screening shows up-regulated wild-type Ppox expression in the fetal blood cells of the yolk sac, with little other expression elsewhere. Subsequent experimental results suggest that Ppox nulls exhibit defects within the proliferating and differentiating mesoderm lineage, including disorganization of vascular endothelial cells in null allantois explant cultures and red blood cell abnormalities in heterozygous dams. Further experiments are aimed at identifying the role fetal blood cells may play in establishing allantoic structure and fusion with the chorion, as well as the possibility of non-apoptotic cell death through loss of heme. Future research on the potential impact of porphyrin accumulation during embryonic development could also greatly aid in the understanding and treatment of variegate porphyria. 

Keywords

development, metabolism, heme biosynthesis, placentation

Research Area

Biological Organisms

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