Beckman et al. (1) reported altered monoaminergic systems and depressive-like behaviors in a line of mice lacking the cellular prion protein PrPC (congenic B10.129-PrnpEdbg/Edbg mice). These mice were derived from gene-targeted 129/Ola embryonic stem cells and were subsequently crossed to C57BL/10SnJ mice. Consequently, the genomic region of B10.129-PrnpEdbg/Edbg mice flanking the targeted Prnp locus contains a stretch of up to 47.4 Mb isogenic to 129/Ola (2). In this region, any genes polymorphic between the 129/Ola and C57BL/10SnJ strains will display 129/Ola allelotypes (2). This genetic anomaly represents a systematic confounder when congenic knock-out mice are compared with wild-type mice of the back-crossing strain, even when using littermates from heterozygous breedings (2). This phenomenon, intrinsic to all congenic knock-out mice, is known as the flanking gene problem.
The genetic background has a strong influence on depression-related behavior in mice (3). Numerous studies have identified multiple genes and quantitative trait loci controlling monoaminergic systems and depressive-like behaviors. Crucially, these include Sirpa, which is linked to Prnp (genetic distance: approximately 2 centimorgans), is polymorphic between C57BL and 129 strains, and is a known genetic confounder of studies with Prnp−/− mice (4, 5).
For the above reasons, the published data (1) do not allow conclusive determination of whether the phenotypes observed are caused by the ablation of Prnp, by the Sirpa polymorphism discussed above, or by other sequence polymorphisms in the genomic region flanking Prnp. The conclusion that PrPC participates in the modulation of monoaminergic systems and depressive-like behavior is therefore unwarranted.
References
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