Nek9-flox Mouse

NEK9, or NIMA-related kinase 9, is involved in multiple biological functions. It plays a role in spindle assembly, controlling chromosome alignment and centrosome separation [4,7]. It is also part of pathways related to ciliogenesis, cell-cycle progression, and autophagy. NEK9 is crucial in the microtubule polymerization, chromosome alignment, and mitosis as part of the NEK9-EG5 axis [3].

In terms of core findings, in mice, mutation in the LC3-interacting region (LIR) of NEK9 impairs in vivo cilia formation in the kidneys, suggesting that NEK9 regulates ciliogenesis by acting as an autophagy adaptor for MYH9, which inhibits ciliogenesis through actin network stabilization [1]. In breast cancer, immunohistochemistry analysis shows decreased Nek9 expression in invasive ductal carcinoma compared to benign breast lesions, and this decrease is associated with larger tumor size, high grade, and high Ki-67 index [4]. In gastric cancer, NEK9 directly regulates cell motility and RhoA activation by phosphorylating ARHGEF2, and is regulated by miR-520f-3p, which is transcriptionally suppressed by IL-6-mediated activation of STAT3 [2]. In colon cancer, overexpression of the NEK9-EG5 axis is associated with distant metastasis [3]. In pancreatic cancer, USP19 stabilizes NEK9 via deubiquitination, and NEK9 phosphorylates Raptor to inhibit the mTORC1 signaling pathway, leading to autophagic cell death [5]. In gastric cancer, CAF-derived SLIT2 activates NEK9, which phosphorylates TRIM28 and CTTN, inducing cytoskeletal reorganization and cell metastasis [6]. In p53-inactivated cancer cells, depletion of NEK9 selectively inhibits proliferation both in vitro and in vivo, causing cell-cycle arrest in G1 phase with senescence-like features [8]. Also, three novel pathogenic variants of NEK9 were detected in neonatal patients with arthrogryposis [9].

In conclusion, NEK9 is essential for various biological processes such as ciliogenesis, cell-cycle regulation, and autophagy. Model-based research, especially in mouse models, has revealed its significant roles in diseases including kidney cilia-related disorders, breast, gastric, colon, pancreatic cancers, and in p53-related cancer cell proliferation as well as neonatal arthrogryposis. Understanding NEK9's functions provides insights into disease mechanisms and potential therapeutic targets.