Dusp15, also known as VHY, is an atypical dual-specificity phosphatase enzyme. It is thought to be activated by myelin regulatory factor (MyRF) and plays a role in oligodendrocyte differentiation [1,6]. It is also involved in multiple signaling pathways such as Jak1-mediated STAT3 activation, Notch signaling, and regulation of extracellular-regulated protein kinase (ERK) [2,3,4,8]. Dusp15 is of significance in various biological processes and diseases including autism, drug addiction, and potentially diabetic cardiomyopathy [4,5,7,9].

In Myrf conditional knock-out (CKO) mouse models, Dusp15 expression was lower in the hippocampus. However, attentional abilities and object recognition memory remained intact, suggesting that these functions are not directly affected by reduced oligodendrogenesis and hippocampal Dusp15 expression [1]. In morphine-related studies, Dusp15 in the nucleus accumbens was found to be a negative regulator of morphine-associated contextual memory. Intra-nucleus accumbens (NAc) infusions of AAV-Dusp15 (overexpression) prevented morphine-induced conditioned place preference (CPP) expression, facilitated extinction, inhibited reinstatement, and abolished ERK activation [4].

In summary, Dusp15 is a key regulator in oligodendrocyte differentiation and involved in multiple signaling pathways. Mouse models, especially Myrf CKO and morphine-treated mice, have provided insights into its role in neurological functions and drug-related behaviors. The identification of Dusp15 as potentially associated with autism and diabetic cardiomyopathy also indicates its importance in understanding these disease mechanisms.

References:

1. Rawlings-Mortimer, Florence, Gullino, L Sophie, Rühling, Sebastian, Barkus, Chris, Johansen-Berg, Heidi. 2023. DUSP15 expression is reduced in the hippocampus of Myrf knock-out mice but attention and object recognition memory remain intact. In PloS one, 18, e0281264. doi:10.1371/journal.pone.0281264. https://pubmed.ncbi.nlm.nih.gov/36730342/

2. Kikkawa, Kazuna, Matsuda, Tadashi, Fujimuro, Masahiro, Sekine, Yuichi. . The Atypical Dual Specificity Phosphatase DUSP15 Regulates Jak1-Mediated STAT3 Activation. In Biological & pharmaceutical bulletin, 47, 1487-1493. doi:10.1248/bpb.b24-00314. https://pubmed.ncbi.nlm.nih.gov/39261048/

3. Bhore, Noopur, Wang, Bo-Jeng, Wu, Po-Fan, Yang, Ding-I, Liao, Yung-Feng. 2021. Dual-Specificity Phosphatase 15 (DUSP15) Modulates Notch Signaling by Enhancing the Stability of Notch Protein. In Molecular neurobiology, 58, 2204-2214. doi:10.1007/s12035-020-02254-0. https://pubmed.ncbi.nlm.nih.gov/33417224/

4. Qiao, Xiaomeng, Zhu, Yongsheng, Dang, Wei, Shi, Yuhui, Zhang, Lirong. 2020. Dual-specificity phosphatase 15 (DUSP15) in the nucleus accumbens is a novel negative regulator of morphine-associated contextual memory. In Addiction biology, 26, e12884. doi:10.1111/adb.12884. https://pubmed.ncbi.nlm.nih.gov/32043707/

5. Tian, Ye, Wang, Lifang, Jia, Meixiang, Liu, Jing, Zhang, Dai. 2016. Association of oligodendrocytes differentiation regulator gene DUSP15 with autism. In The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 18, 143-150. doi:10.1080/15622975.2016.1178395. https://pubmed.ncbi.nlm.nih.gov/27223645/

6. Muth, Katharina N, Piefke, Sandra, Weider, Matthias, Wegner, Michael, Küspert, Melanie. 2016. The Dual-specificity phosphatase Dusp15 is regulated by Sox10 and Myrf in Myelinating Oligodendrocytes. In Glia, 64, 2120-2132. doi:10.1002/glia.23044. https://pubmed.ncbi.nlm.nih.gov/27532821/

7. Fang, Fang, Ge, Minxia, Liu, Jun, Xu, Liwei, Shao, Lina. 2021. Association between Genetic Variants in DUSP15, CNTNAP2, and PCDHA Genes and Risk of Childhood Autism Spectrum Disorder. In Behavioural neurology, 2021, 4150926. doi:10.1155/2021/4150926. https://pubmed.ncbi.nlm.nih.gov/34257739/

8. Rodríguez-Molina, José F, Lopez-Anido, Camila, Ma, Ki H, Weider, Matthias, Svaren, John. 2017. Dual specificity phosphatase 15 regulates Erk activation in Schwann cells. In Journal of neurochemistry, 140, 368-382. doi:10.1111/jnc.13911. https://pubmed.ncbi.nlm.nih.gov/27891578/

9. Zhu, Lingling, Dong, Ya, Guo, Hang, Hu, Yonghui, Pan, Congqing. 2025. Murine Model Insights: Identifying Dusp15 as a Novel Biomarker for Diabetic Cardiomyopathy Uncovered Through Integrated Omics Analysis and Experimental Validation. In Diabetes, metabolic syndrome and obesity : targets and therapy, 18, 515-527. doi:10.2147/DMSO.S501563. https://pubmed.ncbi.nlm.nih.gov/39990179/