Rasd2, also known as Ras homolog enriched in striatum, encodes a Ras-related GTP-binding protein. It is involved in modulating dopaminergic neurotransmission, especially in the striatum, and is associated with pathways related to dopamine D2 receptor (DRD2) transmission [4,2,3]. Rasd2 has been shown to be important in multiple physiological and pathophysiological processes, such as psychiatric disorders, and its study using genetic models can provide insights into its functions [4,2,3,5].

In ovariectomized mice, Rasd2 overexpression in the hippocampus alleviated depression-like behaviors and increased DRD2 expression. Acute fasting-induced antidepressant-like effects in these mice were mediated by Rasd2 through upregulating DRD2 and related proteins, and this effect could be blocked by DRD2 antagonists [2]. In mice exposed to 5-day unpredictable mild stress, overexpression of Rasd2 in the nucleus accumbens core alleviated stress-induced depression-like behaviors and activated the DRD2-cAMP-PKA-DARPP-32 signaling pathway. Also, activation of the prelimbic cortex-nucleus accumbens core circuit glutaminergic projection increased DRD2-and Rasd2-positive neurons in the nucleus accumbens and alleviated depression-like behaviors [3]. In knockout mice, lack of Rasd2 led to deficits in basal prepulse inhibition and enhanced sensitivity to motor stimulation by amphetamine and phencyclidine, suggesting its role in cerebral circuitry dysfunction related to schizophrenia-like behaviors [4]. In uveal melanoma cells, silencing Rasd2 dampened cell growth, migration, invasion, and in vivo tumor growth and lung metastasis, and it was found to regulate epithelial-mesenchymal transition and glycolysis, with knockdown suppressing UVM cell metabolism and expression of glycolysis-related genes [1]. In thyroid cancer cells, genetic silencing of Rasd2 impaired malignant phenotypes such as proliferation, invasion, and glycolytic activity [6].

In conclusion, Rasd2 plays crucial roles in multiple biological processes and disease conditions. Model-based research, especially using gene knockout mouse models, has revealed its significance in psychiatric disorders like depression and schizophrenia-related behaviors, as well as in cancer development and metastasis such as in uveal melanoma and thyroid cancer. Understanding Rasd2 can potentially lead to new therapeutic strategies for these diseases.

References:

1. Xie, Meng, Xin, Chun. 2022. RASD2 promotes the development and metastasis of uveal melanoma via enhancing glycolysis. In Biochemical and biophysical research communications, 610, 92-98. doi:10.1016/j.bbrc.2022.04.060. https://pubmed.ncbi.nlm.nih.gov/35461072/

2. Cheng, Ziqian, Zhang, Chaohe, Zhao, Fangyi, Cui, Ranji, Li, Bingjin. . Rasd2 Mediates Acute Fasting-Induced Antidepressant-Like Effects via Dopamine D2 Receptor Activation in Ovariectomized Mice. In The international journal of neuropsychopharmacology, 26, 217-229. doi:10.1093/ijnp/pyac082. https://pubmed.ncbi.nlm.nih.gov/36566472/

3. Cheng, Ziqian, Zhao, Fangyi, Piao, Jingjing, Cui, Ranji, Li, Bingjin. 2024. Rasd2 regulates depression-like behaviors via DRD2 neurons in the prelimbic cortex afferent to nucleus accumbens core circuit. In Molecular psychiatry, 30, 435-449. doi:10.1038/s41380-024-02684-5. https://pubmed.ncbi.nlm.nih.gov/39097664/

4. Vitucci, Daniela, Di Giorgio, Annabella, Napolitano, Francesco, Bertolino, Alessandro, Usiello, Alessandro. 2015. Rasd2 Modulates Prefronto-Striatal Phenotypes in Humans and 'Schizophrenia-Like Behaviors' in Mice. In Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology, 41, 916-27. doi:10.1038/npp.2015.228. https://pubmed.ncbi.nlm.nih.gov/26228524/

5. Liu, Yu-Li, Fann, Cathy Shen-Jang, Liu, Chih-Min, Tsuang, Ming T, Hwu, Hai-Gwo. 2008. RASD2, MYH9, and CACNG2 genes at chromosome 22q12 associated with the subgroup of schizophrenia with non-deficit in sustained attention and executive function. In Biological psychiatry, 64, 789-96. doi:10.1016/j.biopsych.2008.04.035. https://pubmed.ncbi.nlm.nih.gov/18571626/

6. Li, Xiao-Yu, Sun, Jian-Ping, Guo, Hao, Yu, Na, Li, Qing-Huai. 2025. Modulation of RASD2 by miRNA-485-5p Drives Thyroid Cancer Progression and Metastasis. In The Kaohsiung journal of medical sciences, , e70028. doi:10.1002/kjm2.70028. https://pubmed.ncbi.nlm.nih.gov/40289764/