Unexpected failure of rod bipolar cell targeting using L7Cre-2 mice

Utilizing cell type-specific knockout mice has been an excellent tool for decades not only to explore the role of a gene in a specific cell, but also to unravel the underlying mechanism in diseases. To investigate the mechanistic association between dysfunction of the peroxisomal protein multifunctional protein 2 (MFP2) and retinopathy, we generated and phenotyped multiple transgenic mouse models with global or cell type-specific MFP2 deletion. These studies pointed to a potential role of MFP2 specifically in rod bipolar cells. To explore this, we aimed to create rod bipolar cell specific knockout mice of Mfp2 by crossing Mfp2(L/L) mice with L7Cre-2 mice (also known as PCP2Cre), generating L7-Mfp2(-/-) mice. L7Cre-2 mice express Cre recombinase under the control of the L7 promoter, which is believed to be exclusively expressed in rod bipolar cells and cerebellar Purkinje cells. Un-expectedly, only sporadic Cre activity was observed in the rod bipolar cells of L7-Mfp2(-/-) mice, despite efficient Cre recombination in cerebellar Purkinje cells. Moreover, a variable fraction of photoreceptors was targeted, which does not correspond with the supposed specificity of L7Cre-2 mice. These observations indicate that L7Cre-2 mice can be exploited to manipulate Purkinje cells in the cerebellum, whereas they cannot be used to generate rod bipolar cell specific knockout mice. For this aim, we suggest utilizing an independently generated mouse line named BAC-L7-IRES-Cre.

Automated summary

Using cell type-specific knockout mice has been a valuable tool for studying the role of genes in specific cells and understanding disease mechanisms. In this study, multiple transgenic mouse models with global or cell type-specific deletion of MFP2 were generated and phenotyped to investigate its association with retinopathy. Unexpectedly, the L7Cre-2 mouse model did not show the expected specificity in generating rod bipolar cell specific knockout mice. Instead, the authors suggest using the independently generated BAC-L7-IRES-Cre mouse line for this purpose.