Ptpn20 Deletion in H-tx Rats Facilitates Cotransporter-mediated Water Transport in the Choroid Plexus: Evidence of Genetic Risk for Hydrocephalus in an Experimental Study

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, encompassing the Ptpn20 gene, without change in most non-hydrocephalic H-Tx rats. Ptpn20 -knockout ( Ptpn20 -/- ) mice were generated and found to develop ventriculomegaly. Furthermore, high expression of phosphorylated Na-K-Cl cotransporter 1 (pNKCC1) was identified in the choroid plexus (CP) epithelium of mice lacking Ptpn20 . Conclusions The high level of pNKCC1 in CP epithelium may cause the 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.