Dusp15-flox Mouse

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. It is involved in multiple signaling pathways, such as Jak1-STAT3, Notch, and extracellular-regulated protein kinase (ERK) pathways, and is associated with various biological processes and diseases [1,2,3,4]. Genetic models, like mouse models, are valuable for studying its functions.

In Myrf conditional knock-out (CKO) mice, Dusp15 expression was lower in the hippocampus, yet attentional abilities and object recognition memory remained intact, suggesting that reduced oligodendrogenesis and hippocampal Dusp15 expression do not impact these functions [1]. In Hepa1-6 cells, Dusp15 knockdown decreased leukemia inhibitory factor (LIF)-induced Socs3 mRNA expression and STAT3 translocation, indicating it functions as a positive feedback regulator in the Jak1/STAT3 signaling cascade [2]. Overexpression of Dusp15 in cells increased the steady-state levels of recombinant Notch protein and its cleaved product, revealing a DUSP15-ERK1/2-Notch signaling axis potentially involved in neuronal differentiation and neurological disease [3]. In the nucleus accumbens of mice, Dusp15 was decreased during morphine-conditioned place preference (CPP) expression and reinstatement. Overexpression of Dusp15 in the nucleus accumbens prevented morphine-induced CPP, facilitated extinction, inhibited reinstatement, and abolished ERK activation, suggesting it could be a therapeutic target for drug addiction [4]. In Chinese Han population studies, genetic variants in Dusp15 were associated with autism spectrum disorder (ASD) risk [5,7]. In oligodendrocytes, Sox10 and Myrf cooperate to activate Dusp15, and knockdown of Dusp15 reduced expression of early and late differentiation markers, while overexpression increased it transiently [6]. In Schwann cells, Dusp15 was necessary for full activation of Erk1/2 phosphorylation and repressed expression of several myelin genes [8]. Also, Dusp15 expression was downregulated in high-glucose cultured cardiomyocytes and diabetic cardiomyopathy (DCM) animal models, suggesting its potential role in DCM pathogenesis [9].

In conclusion, Dusp15 is a key regulator in multiple biological processes. Through model-based research, especially KO/CKO mouse models, it has been shown to be involved in oligodendrocyte and Schwann cell differentiation, regulation of various signaling pathways, and is associated with diseases like autism, drug addiction, and diabetic cardiomyopathy. These findings provide valuable insights into understanding biological functions and disease mechanisms related to Dusp15.