Cldn1-KO Mouse

CLDN1, encoding the transmembrane protein claudin-1, is a critical component of tight junctions in various tissues. Tight junctions are crucial for maintaining the permeability and integrity of epithelial cell barriers. Claudin-1 also participates in multiple biological processes such as cell-cell adhesion [5].

In preeclampsia, downregulation of CLDN1 in trophoblast cells is associated with inhibited proliferation, induced apoptosis, impaired invasion, and abnormal endovascular trophoblast differentiation. Knockdown of CLDN1 in HTR-8/SVneo cells led to these effects, while overexpression reversed them. Also, BIRC3 was identified as potentially downstream of CLDN1 in apoptosis regulation [1,4].

In keratinocytes, CLDN1 knockout (CLDN1 KO) led to reduced epidermal barrier function, decreased expression of barrier-related genes, abnormal stratification, and increased proliferative keratinocytes in the basale layer, highlighting its role in epidermal barrier formation and epidermal stratification [2].

In airway smooth muscle cells, CLDN1 knockdown inhibited proliferation, migration, invasion, and inflammation induced by PDGF-BB, suggesting its role in airway remodeling in asthma [3].

In esophageal squamous carcinoma, CLDN1 promoted proliferation and metastasis by triggering autophagy through the AMPK/STAT1/ULK1 signaling pathway [5].

In colorectal cancer, CLDN1 interacted with EPHA2 to promote cancer stemness and chemoresistance [6].

In lung adenocarcinoma, CLDN1 repressed cancer progression via the CLDN1-EPHB6-ERK1/2-SLUG axis, and DNA methylation maintained its expression [7].

Pathogenic variants in CLDN1, like the missense variant c.242G>A (p.Arg81His), led to autosomal recessive congenital ichthyosis and ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) syndrome, with disrupted tight-junction architecture [8,9].

In triple-negative breast cancer, a CLDN1-negative phenotype predicted poor prognosis, being an independent adverse prognostic factor [10].

In summary, CLDN1 plays essential roles in maintaining tissue integrity, regulating cell proliferation, apoptosis, invasion, and differentiation in various biological systems. Studies using CLDN1 KO models have revealed its significance in diseases such as preeclampsia, skin disorders, asthma, multiple cancers, and ILVASC syndrome, providing insights into disease mechanisms and potential therapeutic targets.

References:

1. Zhang, Yu-Chen, Qin, Xiao-Li, Ma, Xiao-Ling, Tian, Fu-Ju, Lin, Yi. 2021. CLDN1 regulates trophoblast apoptosis and proliferation in preeclampsia. In Reproduction (Cambridge, England), 161, 623-632. doi:10.1530/REP-20-0677. https://pubmed.ncbi.nlm.nih.gov/33784242/

2. Arnold, Kimberly A, Moran, Mary C, Shi, Huishan, Smits, Jos P H, Brewer, Matthew G. . CLDN1 knock out keratinocytes as a model to investigate multiple skin disorders. In Experimental dermatology, 33, e15084. doi:10.1111/exd.15084. https://pubmed.ncbi.nlm.nih.gov/38711223/

3. Li, Wei, Liu, Linyan, Duanqing, Ming'ai, Zhou, Min, Yan, Jun. 2023. CLDN1 silencing suppresses the proliferation and migration of airway smooth muscle cells by modulating MMP14. In Autoimmunity, 56, 2281223. doi:10.1080/08916934.2023.2281223. https://pubmed.ncbi.nlm.nih.gov/37964516/

4. Jin, Pingsong, Zhou, Yijie, Liu, Zheng, Chen, Xuehai, Qi, Hongbo. 2023. Downregulation of CLDN1 impairs trophoblast invasion and endovascular trophoblast differentiation in early-onset preeclampsia. In Placenta, 140, 20-29. doi:10.1016/j.placenta.2023.07.010. https://pubmed.ncbi.nlm.nih.gov/37523840/

5. Wu, Jian, Gao, FengXia, Xu, Tao, Zhou, Biao, Dai, TianYang. 2019. CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling. In Journal of cellular physiology, 235, 2245-2259. doi:10.1002/jcp.29133. https://pubmed.ncbi.nlm.nih.gov/31498437/

6. Primeaux, Mark, Liu, Xiangdong, Gowrikumar, Saiprasad, Singh, Amar B, Dhawan, Punita. 2023. Claudin-1 interacts with EPHA2 to promote cancer stemness and chemoresistance in colorectal cancer. In Cancer letters, 579, 216479. doi:10.1016/j.canlet.2023.216479. https://pubmed.ncbi.nlm.nih.gov/37924938/

7. Wu, Jia-En, Wu, Yi-Ying, Tung, Chia-Hao, Chen, Yuh-Ling, Hong, Tse-Ming. 2020. DNA methylation maintains the CLDN1-EPHB6-SLUG axis to enhance chemotherapeutic efficacy and inhibit lung cancer progression. In Theranostics, 10, 8903-8923. doi:10.7150/thno.45785. https://pubmed.ncbi.nlm.nih.gov/32754286/

8. Mohamad, Janan, Samuelov, Liat, Assaf, Sari, Sarig, Ofer, Sprecher, Eli. 2022. Autosomal recessive congenital ichthyosis caused by a pathogenic missense variant in CLDN1. In American journal of medical genetics. Part A, 188, 2879-2887. doi:10.1002/ajmg.a.62924. https://pubmed.ncbi.nlm.nih.gov/35920354/

9. Eskin-Schwartz, Marina, Dolgin, Vadim, Didkovsky, Elena, Zilberman, Uri, Birk, Ohad S. 2023. CLDN1 Arg81His founder variant causes ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis (ILVASC) syndrome in Moroccan Jews. In Clinical genetics, 105, 44-51. doi:10.1111/cge.14432. https://pubmed.ncbi.nlm.nih.gov/37814412/

10. Ma, Fei, Ding, Xiaoyan, Fan, Ying, Lu, Ning, Xu, Binghe. 2014. A CLDN1-negative phenotype predicts poor prognosis in triple-negative breast cancer. In PloS one, 9, e112765. doi:10.1371/journal.pone.0112765. https://pubmed.ncbi.nlm.nih.gov/25393310/