GIGYF1, short for GRB10 interacting GYF protein 1, binds to the N-terminal region of Grb10 and is involved in regulating multiple signaling pathways [6]. It has been implicated in processes such as mRNA translation initiation regulation, mRNA decay, and cytokine mRNA regulation [3,4,5]. For example, it can robustly repress cellular mRNA translation through disrupting the eIF3-eIF4G1 interaction [3].

GIGYF1 disruption has been extensively studied in genetic models. In conditional KO mouse models, haploinsufficiency in the developing brain led to social impairments without significant cognitive impairments, while homozygous KO mice showed more severe social and cognitive disabilities [1]. GIGYF1 deficiency also led to a reduction in upper-layer cortical neurons, with changes in neural progenitor cell proliferation and differentiation [1]. It was found that GIGYF1 regulates the recycling of IGF-1R to the cell surface, and its KO disrupted the IGF-1R/ERK signaling pathway [1]. In zebrafish and mouse knockout models, loss of GIGYF1 caused similar behavioral effects, including elevated anxiety and reduced social engagement, and excitatory neuron-specific Gigyf1 knockout mice recapitulated increased repetitive behaviors and impaired social memory [2].

In conclusion, GIGYF1 is crucial for normal neurodevelopment and behavior, potentially through regulating synaptic transmission and IGF-1R recycling. Studies using KO/CKO mouse models have significantly advanced our understanding of its role in autism spectrum disorder and other neurodevelopmental disorders [1,2].

References:

1. Chen, Guodong, Yu, Bin, Tan, Senwei, Xia, Kun, Guo, Hui. 2022. GIGYF1 disruption associates with autism and impaired IGF-1R signaling. In The Journal of clinical investigation, 132, . doi:10.1172/JCI159806. https://pubmed.ncbi.nlm.nih.gov/35917186/

2. Ding, Zijiao, Huang, Guiyang, Wang, Tianyun, Jiang, Man, Xiong, Bo. 2023. Genetic Ablation of GIGYF1, Associated With Autism, Causes Behavioral and Neurodevelopmental Defects in Zebrafish and Mice. In Biological psychiatry, 94, 769-779. doi:10.1016/j.biopsych.2023.02.993. https://pubmed.ncbi.nlm.nih.gov/36924980/

3. Choi, Jung-Hyun, Luo, Jun, Hesketh, Geoffrey G, Sonenberg, Nahum, Jafarnejad, Seyed Mehdi. 2024. Repression of mRNA translation initiation by GIGYF1 via disrupting the eIF3-eIF4G1 interaction. In Science advances, 10, eadl5638. doi:10.1126/sciadv.adl5638. https://pubmed.ncbi.nlm.nih.gov/39018414/

4. Weber, Ramona, Chung, Min-Yi, Keskeny, Csilla, Izaurralde, Elisa, Igreja, Cátia. . 4EHP and GIGYF1/2 Mediate Translation-Coupled Messenger RNA Decay. In Cell reports, 33, 108262. doi:10.1016/j.celrep.2020.108262. https://pubmed.ncbi.nlm.nih.gov/33053355/

5. Tollenaere, Maxim A X, Tiedje, Christopher, Rasmussen, Simon, Gaestel, Matthias, Bekker-Jensen, Simon. . GIGYF1/2-Driven Cooperation between ZNF598 and TTP in Posttranscriptional Regulation of Inflammatory Signaling. In Cell reports, 26, 3511-3521.e4. doi:10.1016/j.celrep.2019.03.006. https://pubmed.ncbi.nlm.nih.gov/30917308/

6. Zhu, Linqi, Yao, Zhendong, Luo, Qingxin, Shao, Shihe, Cui, Feilun. 2023. Low Expression of GIGYF1 Inhibits Metastasis, Proliferation, and Promotes Apoptosis and Autophagy of Gastric Cancer Cells. In International journal of medical sciences, 20, 1038-1045. doi:10.7150/ijms.82719. https://pubmed.ncbi.nlm.nih.gov/37484805/