Brain transcriptional stability upon prion protein-encoding gene invalidation in zygotic or adult mouse

Abstract

BackgroundThe physiological function of the prion protein remains largely elusive while its key role in prion infection has been expansively documented. To potentially assess this conundrum, we performed a comparative transcriptomic analysis of the brain of wild-type mice with that of transgenic mice invalidated at this locus either at the zygotic or at the adult stages.ResultsOnly subtle transcriptomic differences resulting from the Prnp knockout could be evidenced, beside Prnp itself, in the analyzed adult brains following microarray analysis of 24 109 mouse genes and QPCR assessment of some of the putatively marginally modulated loci. When performed at the adult stage, neuronal Prnp disruption appeared to sequentially induce a response to an oxidative stress and a remodeling of the nervous system. However, these events involved only a limited number of genes, expression levels of which were only slightly modified and not always confirmed by RT-qPCR. If not, the qPCR obtained data suggested even less pronounced differences.ConclusionsThese results suggest that the physiological function of PrP is redundant at the adult stage or important for only a small subset of the brain cell population under classical breeding conditions. Following its early reported embryonic developmental regulation, this lack of response could also imply that PrP has a more detrimental role during mouse embryogenesis and that potential transient compensatory mechanisms have to be searched for at the time this locus becomes transcriptionally activated.

Neuritogenesis: the prion protein controls β1 integrin signaling activity

“…The more dramatic phenotypic consequence of PrP C depletion in 1C11 neuroectodermal cells, as well as PC12 cells, vs. other neuronal cell cultures might be explained by the origin of the latter, which all derive from PrP‐knockout mice (10, 12, 13, 40). PrP C deficiency in these mice likely mobilizes compensatory mechanisms, as previously suggested (41, 42), and in line with the absence of an overt phenotype in PrP KO mice (43). One possible candidate for such compensation could be the PrP‐related protein Shadoo.…”

Prion Protein and Shadoo Are Involved in Overlapping Embryonic Pathways and Trophoblastic Development

“…However, since then, evidence has been published highlighting other differences than Prnp between these two genetic backgrounds. Prnp -physically linked 129-derived loci were reported to be conserved in FVB/N Prnp KO mice alongside the Prnp locus itself [26]. Although unlikely, such non- Prnp loci could be involved in the observed lethality associated with Sprn knockdown in FVB/N Prnp KO embryos.…”

The biological function of the cellular prion protein: an update

“…Transcriptomic analysis of PrP C knockout embryos showed several differentially expressed genes (DEGs), while the number of DEGs in brains of adult PrP C -deficient mice is almost negligible [42, 109]. Interestingly, the number of DEGs is higher in brains where PrP C had been knocked out postnatally, suggesting that the function of PrP C may be compensated for by other proteins during development [110]. To date, only a few in vivo studies on the role of PrP C in CNS development are available.…”