Regulation of Embryonic Cell Adhesion by the Prion Protein

Abstract

Prion proteins (PrPs) are key players in fatal neurodegenerative disorders, yet their physiological functions remain unclear, as PrP knockout mice develop rather normally. We report a strong PrP loss-of-function phenotype in zebrafish embryos, characterized by the loss of embryonic cell adhesion and arrested gastrulation. Zebrafish and mouse PrP mRNAs can partially rescue this knockdown phenotype, indicating conserved PrP functions. Using zebrafish, mouse, and Drosophila cells, we show that PrP: (1) mediates Ca+2-independent homophilic cell adhesion and signaling; and (2) modulates Ca+2-dependent cell adhesion by regulating the delivery of E-cadherin to the plasma membrane. In vivo time-lapse analyses reveal that the arrested gastrulation in PrP knockdown embryos is due to deficient morphogenetic cell movements, which rely on E-cadherin–based adhesion. Cell-transplantation experiments indicate that the regulation of embryonic cell adhesion by PrP is cell-autonomous. Moreover, we find that the local accumulation of PrP at cell contact sites is concomitant with the activation of Src-related kinases, the recruitment of reggie/flotillin microdomains, and the reorganization of the actin cytoskeleton, consistent with a role of PrP in the modulation of cell adhesion via signaling. Altogether, our data uncover evolutionarily conserved roles of PrP in cell communication, which ultimately impinge on the stability of adherens cell junctions during embryonic development.

The regulation of cell-cell adhesion during epithelial-mesenchymal transition, motility and tumor progression

“…90,91 In association with prion protein (PrP), reggies/ flotillins control activation of Src kinases and the presence of receptor tyrosine kinases such as EGFR at the membrane. 92 Reggies contribute to the internalization and turnover of Ecadherin. Together with PrP they target the recycling of E-cadherin to the AJs and its binding to catenins for the maintenance of cell adhesion (Fig.…”

Knockout of the prion protein (PrP)-like Sprn gene does not produce embryonic lethality in combination with PrP C -deficiency

“…Furthermore, other hypotheses that also seek to explain the properties of internal PrP deletions neither invoke a PrP paralog nor consider action in embryonic development (44). Rather, although there is data that the zebrafish PrP-1 gene may modulate cell adhesion and serve a neurodevelopmental role (45), there is a broad consensus that PrP C in mammals may serve to protect or maintain neurons in adult life (46). The same concept may apply to Sho as well, and experiments to appraise this possibility are underway.…”

Prion potency in stem cells biology

“…23 The first dramatic phenotypes resulting from PrP loss-offunction were observed in zebrafish, in which the development of early and late structures is severely affected. 24 Notably, early knockdown of PrP in fish embryos is lethal, characterized by the loss of embryonic cell adhesion and arrested gastrulation, and the phenotype can be partially rescued by expression of mouse PrP.…”