Arhgef18, also known as p114RhoGEF, is a Rho guanine nucleotide exchange factor. It is crucial for regulating the cytoskeleton and adhesion through activating Rho GTPases. Arhgef18 is involved in pathways like PKA/CREB signaling, NF-κB signaling, and RhoA-Rock2 signaling, which are vital for processes such as tissue development, immune response, and maintaining cell polarity [1,2,3]. Genetic models, especially KO/CKO mouse models, are valuable for studying its functions.

In mouse models, Arhgef18 deficiency leads to abnormal syncytiotrophoblast differentiation and placenta development, as it is required for PKA-induced actomyosin remodeling and CREB-driven gene expression essential for trophoblast cell-cell fusion [1]. In medaka fish, mutations of Arhgef18 affect the apicobasal polarity of the retinal neuroepithelium, disrupting the ratio of neurogenic to proliferative cell divisions [3]. In endothelial cells, ARHGEF18 phosphorylation and activity, modulated by shear stress, are necessary for maintaining endothelial tight junctions and controlling vascular permeability in vivo [4]. In humans, biallelic mutations in ARHGEF18 cause adult-onset retinal degeneration [5].

In conclusion, Arhgef18 plays essential roles in multiple biological processes, including placenta morphogenesis, maintaining neuro-epithelial polarity, and controlling endothelial tight junctions. The study of Arhgef18 using KO/CKO mouse models and other genetic models has provided insights into its functions in these processes and its implications in diseases such as retinal degeneration.

References:

1. Beal, Robert, Alonso-Carriazo Fernandez, Ana, Grammatopoulos, Dimitris K, Matter, Karl, Balda, Maria S. 2021. ARHGEF18/p114RhoGEF Coordinates PKA/CREB Signaling and Actomyosin Remodeling to Promote Trophoblast Cell-Cell Fusion During Placenta Morphogenesis. In Frontiers in cell and developmental biology, 9, 658006. doi:10.3389/fcell.2021.658006. https://pubmed.ncbi.nlm.nih.gov/33842485/

2. Yin, Jiying, Diao, Naichao, Tian, Tian, Shi, Kun, Du, Rui. 2023. ARHGEF18 can promote BVDV NS5B activation of the host NF-κB signaling pathway by combining with the NS5B-palm domain. In Veterinary microbiology, 291, 109911. doi:10.1016/j.vetmic.2023.109911. https://pubmed.ncbi.nlm.nih.gov/38367539/

3. Herder, Cathrin, Swiercz, Jakub M, Müller, Claudia, Wittbrodt, Joachim, Loosli, Felix. 2013. ArhGEF18 regulates RhoA-Rock2 signaling to maintain neuro-epithelial apico-basal polarity and proliferation. In Development (Cambridge, England), 140, 2787-97. doi:10.1242/dev.096487. https://pubmed.ncbi.nlm.nih.gov/23698346/

4. Batta, Surya Prakash Rao, Rio, Marc, Lebot, Corentin, Loirand, Gervaise, Vion, Anne-Clémence. 2025. ARHGEF18 is a flow-responsive exchange factor controlling endothelial tight junctions and vascular leakage. In Cell reports, 44, 115288. doi:10.1016/j.celrep.2025.115288. https://pubmed.ncbi.nlm.nih.gov/39977269/

5. Arno, Gavin, Carss, Keren J, Hull, Sarah, Balda, Maria S, Webster, Andrew R. 2017. Biallelic Mutation of ARHGEF18, Involved in the Determination of Epithelial Apicobasal Polarity, Causes Adult-Onset Retinal Degeneration. In American journal of human genetics, 100, 334-342. doi:10.1016/j.ajhg.2016.12.014. https://pubmed.ncbi.nlm.nih.gov/28132693/