Mutated SASH1 promotes Mitf expression in a heterozygous mutated SASH1 knock‑in mouse model
| Autor: | Qianfan Liu, Zhixiong Wu, Ding’an Zhou, Dahong Wang, Daoqiu Wu, Lian Chen, Yadong Li, Zexi Xu, Pingsheng Hu, Yinqian Deng, Jiawei Zeng, Jinyun Wang, Xin Wan, Jing Zhang, Hai Huang |
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| Rok vydání: | 2020 |
| Předmět: |
microphthalmia-associated transcription factor
Male 0301 basic medicine Heterozygote mouse model dyschromatosis universalis hereditaria Biology medicine.disease_cause Mice 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Genetics medicine Animals Humans RNA Messenger Gene Transcription factor Cell Nucleus Mice Inbred BALB C Mutation integumentary system Oncogene Tumor Suppressor Proteins Skin Diseases Genetic Articles General Medicine Microphthalmia-associated transcription factor Phenotype Pedigree Cell biology 030104 developmental biology Y551D SASH1 030220 oncology & carcinogenesis Female Signal transduction Pigmentation Disorders Protein Binding Signal Transduction |
| Zdroj: | International Journal of Molecular Medicine |
| ISSN: | 1791-244X 1107-3756 |
| DOI: | 10.3892/ijmm.2020.4652 |
| Popis: | The SAM and SH3 domain-containing 1 (SASH1) genes have been identified as the causal genes of dyschromatosis universalis hereditaria (DUH); these genes cause the pathological phenotypes of DUH, and SASH1 variants have been shown to regulate the abnormal pigmentation phenotype in human skin in various genodermatoses. However, investigations into the mutated SASH1 gene have been limited to in vitro studies. In the present study, to recapitulate the molecular pathological phenotypes of individuals with DUH induced by SASH1 mutations, a heterozygous BALB/c mouse model, in which the human SASH1 c.1654 T>G (p. Tyr 551Asp, Y551D) mutation was knocked in was first generated. The in vivo functional experiments on Y551D SASH1 indicated that the increased expression of microphthalmia-associated transcription factor (Mitf) was uniformly induced in the tails of heterozygous BALB/c mice, and an increased quantity of Mitf-positive epithelial cells was also detected. An increased expression of Mitf- and Mitf-positive cells was also demonstrated in the epithelial tissues of Y551D-SASH1 affected individuals. In the present study, Mitf expression was also found to be increased by Y551D SASH1 in vitro. Taken together, these findings indicate that the upregulation of Mitf is the bona fide effector of the Y551D SASH1-mediated melanogenesis signaling pathway in vivo. SASH1 may function as a scaffold molecule for the assembly of a SASH1-Mitf molecular complex to regulate Mitf expression in the cell nucleus and thus to promote the hyperpigmented phenotype in the pathogenesis of DUH and other genodermatoses related to pigment abnormalities. |
| Databáze: | OpenAIRE |
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