Gdi2, also known as GDP Dissociation Inhibitor 2, is a crucial regulator of Rab GTPase activity, which is involved in intracellular vesicle and membrane trafficking. By inhibiting the dissociation of GDP and the subsequent binding of GTP in Rab proteins, Gdi2 plays a key role in maintaining cellular homeostasis [1,4].

Targeted disruption of Gdi2 in mice reveals its essential role in embryonic development. Complete loss of Gdi2 leads to embryonic lethality, with developmental retardation apparent at E10.5-E14.5, and no viable Gdi2 -/- embryos detected after E14.5. Histological analysis shows extensive cell death and apoptosis, suggesting Gdi2 maintains homeostasis by regulating cell apoptosis [1]. In the 5xFAD mouse model of Alzheimer's disease, neuron-specific knockout of Gdi2 significantly ameliorates cognitive impairment, prevents neuronal loss, reduces senile plaques and astrocyte activation, and decreases Aβ production by regulating APP intracellular transport [2]. In prostate cancer cells, knocking down Gdi2 suppresses cell proliferation but promotes cell apoptosis via the p75NTR signaling pathway [3]. In colorectal cancer, silencing Gdi2 activates the p53 signaling pathway by regulating RAB5A expression, inducing cell cycle arrest and inhibiting cell proliferation, migration, and invasion [5].

In summary, Gdi2 is essential for embryonic development and is involved in various disease conditions. Gene knockout mouse models have been instrumental in revealing its functions in embryonic development, neurodegeneration like in Alzheimer's disease, and cancer. Understanding Gdi2's role provides potential therapeutic targets for these diseases [1,2,3,5].

References:

1. Wu, Yin, Yang, Darong, Chen, Guo-Yun. 2022. Targeted disruption of Gdi2 causes early embryonic lethality. In Placenta, 126, 17-25. doi:10.1016/j.placenta.2022.05.005. https://pubmed.ncbi.nlm.nih.gov/35689892/

2. Wang, Meitian, He, Xiuqing, Li, Jie, Wang, Luwen, Su, Bo. 2024. GDI2 deletion alleviates neurodegeneration and memory loss in the 5xFAD mice model of Alzheimer's disease. In Biochimica et biophysica acta. Molecular basis of disease, 1870, 167093. doi:10.1016/j.bbadis.2024.167093. https://pubmed.ncbi.nlm.nih.gov/38382624/

3. Liu, Chi, Wang, Wei, Lin, Ping, Wang, Nan, Yu, Xiaoguang. 2021. GDI2 is a target of paclitaxel that affects tumorigenesis of prostate cancer via the p75NTR signaling pathway. In Biochemical and biophysical research communications, 562, 119-126. doi:10.1016/j.bbrc.2021.05.015. https://pubmed.ncbi.nlm.nih.gov/34051575/

4. Wu, Y, Chen, G Y. 2024. The Novel Role of GDI2: A Mini-Review. In Annals of medicine and medical research, 7, . doi:. https://pubmed.ncbi.nlm.nih.gov/39831280/

5. Ou, Wen-Ting, Tan, Rong-Jian, Zhai, Jia-Wei, Quan, Zhen-Hao, Zhou, Cai-Jin. 2024. Silencing GDI2 inhibits proliferation, migration and invasion of colorectal cancer through activation of p53 signaling pathway. In Heliyon, 10, e37770. doi:10.1016/j.heliyon.2024.e37770. https://pubmed.ncbi.nlm.nih.gov/39323841/