Potential neuron‐autonomous Purkinje cell degeneration by 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase promoter/Cre‐mediated autophagy impairments

• Published in: The FASEB journal 2021-01, Vol.35 (1), p.e21225-n/a
• Main Authors: Jo, Young Rae, Kim, Hye Ran, Jang, So Young, Go, Hana, Song, Min‐Young, Park, Da Kyeong, Oh, Yuna, Jo, Juyeon, Shin, Yoon Kyung, Lee, Sung Joong, Cheon, Sang‐Myung, Lee, Hyun Kyoung, Lee, Kyung Eun, Kim, Young Hye, Park, Hwan Tae
• Format: Article
• Language: English
• Subjects: CNP; myelination; neurodegeneration; oligodendrocyte; p62
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.202001366RR

Studies of neuroglial interaction largely depend on cell‐specific gene knockout (KO) experiments using Cre recombinase. However, genes known as glial‐specific genes have recently been reported to be expressed in neuroglial stem cells, leading to the possibility that a glia‐specific Cre driver results in unwanted gene deletion in neurons, which may affect sound interpretation. 2′,3′‐Cyclic nucleotide 3′‐phosphodiesterase (CNP) is generally considered to be an oligodendrocyte (OL) marker. Accordingly, Cnp promoter‐controlled Cre recombinase has been used to create OL‐specific gene targeting mice. However, in this study, using Rosa26‐tdTomato‐reporter/Cnp‐Cre mice, we found that many forebrain neurons and cerebellar Purkinje neurons belong to the lineages of Cnp‐expressing neuroglial stem cells. To answer whether gene targeting by Cnp‐Cre can induce neuron‐autonomous defects, we conditionally deleted an essential autophagy gene, Atg7, in Cnp‐Cre mice. The Cnp‐Cre‐mediated Atg7 KO mice showed extensive p62 inclusion in neurons, including cerebellar Purkinje neurons with extensive neurodegeneration. Furthermore, neuronal areas showing p62 inclusion in Cnp‐Cre‐mediated Atg7 KO mice overlapped with the neuronal lineage of Cnp‐expressing neuroglial stem cells. Moreover, Cnp‐Cre‐mediated Atg7‐KO mice did not develop critical defects in myelination. Our results demonstrate that a large population of central neurons are derived from Cnp‐expressing neuroglial stem cells; thus, conditional gene targeting using the Cnp promoter, which is known to be OL‐specific, can induce neuron‐autonomous phenotypes.