Ptpn20 deletion in H-Tx rats enhances phosphorylation of the NKCC1 cotransporter in the choroid plexus: an evidence of genetic risk for hydrocephalus in an experimental study

Springer Science and Business Media LLC - 2022
Hao Xu1, Masakazu Miyajima2, Madoka Nakajima1, Ikuko Ogino1, Kaito Kawamura1, Chihiro Akiba2, Chihiro Kamohara1, Koichiro Sakamoto1, Kostadin Karagiozov1, Eri Nakamura3, Norio Tada3, Hajime Arai1, Akihide Kondo1
1Department of Neurosurgery, Juntendo University Graduate School of Medicine, Hongo Bunkyo-ku, Tokyo, 113-8421, Japan
2Department of Neurosurgery, Juntendo Tokyo Koto Geriatric Medical Center, 3-3-20 Shinsuna, Koto-ku, Tokyo, 136-0075, Japan
3Department of Genetic Analysis Model Laboratory, Juntendo University Graduate School of Medicine, Hongo Bunkyo-ku, Tokyo, 113-8421, Japan

Tóm tắt

Abstract Background Congenital hydrocephalus occurs with some inheritable characteristics, but the mechanisms of its development remain poorly understood. Animal models provide the opportunity to identify potential genetic causes in this condition. The Hydrocephalus-Texas (H-Tx) rat strain is one of the most studied animal models for investigating the causative genetic alterations and analyzing downstream pathogenetic mechanisms of congenital hydrocephalus. Methods Comparative genomic hybridization (CGH) array on non-hydrocephalic and hydrocephalic H-Tx rats was used to identify causative genes of hydrocephalus. Targeted gene knockout mice were generated by CRISPR/Cas9 to study the role of this gene in hydrocephalus. Results CGH array revealed a copy number loss in chromosome 16p16 region in hydrocephalic H-Tx rats at 18 days gestation, encompassing the protein tyrosine phosphatase non-receptor type 20 (Ptpn20), a non-receptor tyrosine phosphatase, without change in most non-hydrocephalic H-Tx rats. Ptpn20-knockout (Ptpn20−/−) mice were generated and found to develop ventriculomegaly at 8 weeks. Furthermore, high expression of phosphorylated Na-K-Cl cotransporter 1 (pNKCC1) was identified in the choroid plexus (CP) epithelium of mice lacking Ptpn20 from 8 weeks until 72 weeks. Conclusions This study determined the chromosomal location of the hydrocephalus-associated Ptpn20 gene in hydrocephalic H-Tx rats. The high level of pNKCC1 mediated by Ptpn20 deletion in CP epithelium may cause overproduction of cerebrospinal fluid and contribute to the formation of hydrocephalus in Ptpn20−/− mice. Ptpn20 may be a potential therapeutic target in the treatment of hydrocephalus.

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