Abstract
Shadoo belongs to the prion protein family, an evolutionary conserved and extensively studied family due to the implication of PrP in Transmissible Spongiform Encephalopathies. However, the biological function of these genes remains poorly understood. While Sprn-knockdown experiments suggested an involvement of Shadoo during mouse embryonic development, Sprn-knockout experiments in 129Pas/C57BL/6J or 129Pas/FVB/NCr mice did not confirm it. In the present study, we analyzed the impact of Sprn gene invalidation in a pure FVB/NJ genetic background, using a zinc finger nuclease approach. The in-depth analysis of the derived knockout transgenic mice revealed a significant increase in embryonic lethality at early post-implantation stages, a growth retardation of young Sprn-knockout pups fed by wild type mice and a lactation defect of Sprn-knockout females. Histological and transcriptional analyses of knockout E7.5 embryos, E14.5 placentas and G7.5 mammary glands revealed specific roles of the Shadoo protein in mouse early embryogenesis, tissue development and differentiation with a potential antagonist action between PrP and Shadoo. This study thus highlights the entanglement between the proteins of the prion family.
Highlights
Shadoo belongs to the prion protein family, an evolutionary conserved and extensively studied family due to the implication of PrP in Transmissible Spongiform Encephalopathies
The Zinc Finger Nuclease (ZFN) target site is located at the start of the Sprn ORF (Fig. 1)
The biological role of the members of the prion family remains mostly unknown, despite intensive researches focusing on PrP due to its major implication in Transmissible Spongiform Encephalopathies (TSE) and potential involvement in other more prevalent neurodegenerative diseases such as Alzheimer’s disease
Summary
Shadoo belongs to the prion protein family, an evolutionary conserved and extensively studied family due to the implication of PrP in Transmissible Spongiform Encephalopathies. While Sprn-knockdown experiments suggested an involvement of Shadoo during mouse embryonic development, Sprn-knockout experiments in 129Pas/ C57BL/6J or 129Pas/FVB/NCr mice did not confirm it. The knockdown of Sprn in 129Pas/FVB/ NCr Prnp-knockout embryos induces a lethal phenotype at early embryonic stages (~E10)[10,11], originating from a trophectoderm-derived compartment developmental failure[11]. Sprn or Sprn/Prnp co-ablation in 129Pas/C57BL/6J or 129Pas/FVB/NCr mice did not reveal embryonic developmental abnormality[12]. These divergent observations, sometimes attributed to genetic compensation in mutated animals[13], questioned the involvement of Shadoo during embryogenesis. Our data suggest antagonist actions of PrP and Shadoo, at least during embryonic stages
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