The Guanine nucleotide exchange factor Vav2（Vav2） is a member of the Vav family that serves as an important regulators for the Rho family of Ras-related GTPases. In the current study, an ortholog（Lj-Vav2） of Vav2 ...The Guanine nucleotide exchange factor Vav2（Vav2） is a member of the Vav family that serves as an important regulators for the Rho family of Ras-related GTPases. In the current study, an ortholog（Lj-Vav2） of Vav2 was identified in the lamprey（Lampetra japonica）. To elucidate the phylogenetic relationship of Vav2, the metazoan genome databases were analyzed to mine the ortholog of Vav. It was found that Vav2 genes were only existed in vertebrates and Lj-Vav2 was the original one found in agnathans. The evolutionary dynamics of conserved motifs of Vav2 were explored using combined amino acid sequence as markers, and it is revealed that the Calponin homology（CH） domain, Dbl-homologous（DH） domain, Pleckstrin homology（PH） domain, Cysteine-rich（C1）domains, Src homology 3（SH3） domains and Src homology 2（SH2） domain were conserved throughout the Vav2 gene family in vertebrates during gene evolution. Relative quantitative real-time PCR analysis showed that the LjVav2 was distributed in the heart, kidney, supraneural myeloid body, liver, gill and lymphocyte-like cells. The LjVav2 was found to be expressed in these tissues, and the level of which was upregulated in lymphocyte-like cells after the animal was stimulated with LPS. These results indicated that the Lj-Vav2 might be involved in the immune response of lymphocyte-like cells in lamprey. Meanwhile, our findings provided a foundation for further investigation of the function of Lj-Vav2 in the primary vertebrate.展开更多
Primary open-angle glaucoma(POAG)is the leading cause of irreversible blindness worldwide,primarily due to the degeneration of retinal ganglion cells(RGCs).In this study,we reported vav guanine nucleotide exchange fac...Primary open-angle glaucoma(POAG)is the leading cause of irreversible blindness worldwide,primarily due to the degeneration of retinal ganglion cells(RGCs).In this study,we reported vav guanine nucleotide exchange factor 2(VAV2)as a POAG-associated gene.Through whole exome sequencing(WES)of 398 Han Chinese POAG patients and 2,010 controls,we discovered nine rare VAV2 variants linked to POAG(P_burden=1.40×10^(-6)).Functional analyses revealed that these variants disrupted normal VAV2 protein function,leading to compromised cytoskeletal organization in human trabecular meshwork cells and impaired axonal growth in the 661W cell line.In vivo,Vav2 knockout mice exhibited key POAG features,including increased intraocular pressure(IOP),abnormal trabecular meshwork structure,reduced visual sensitivity,and RGC loss.This study also implicated VAV2 in the modulation of the Rho signaling pathway,which is essential for maintaining trabecular meshwork integrity and neuronal function.Taken together,this research identified VAV2 as a candidate gene for POAG and suggests VAV2 as a potential target for genetic screening of POAG diagnostics.展开更多
基金The National Basic Research Program of China(973 Program)under contract No.2013CB835304the National Marine Public Projects under contract No.201305016+2 种基金the National Natural Science Foundation of China(General Program)under contract No.31601865the Dalian Science and Technology Program under contract No.2013E11SF056the Education Department of the General Scientific Research Project under contract No.L201683651
文摘The Guanine nucleotide exchange factor Vav2（Vav2） is a member of the Vav family that serves as an important regulators for the Rho family of Ras-related GTPases. In the current study, an ortholog（Lj-Vav2） of Vav2 was identified in the lamprey（Lampetra japonica）. To elucidate the phylogenetic relationship of Vav2, the metazoan genome databases were analyzed to mine the ortholog of Vav. It was found that Vav2 genes were only existed in vertebrates and Lj-Vav2 was the original one found in agnathans. The evolutionary dynamics of conserved motifs of Vav2 were explored using combined amino acid sequence as markers, and it is revealed that the Calponin homology（CH） domain, Dbl-homologous（DH） domain, Pleckstrin homology（PH） domain, Cysteine-rich（C1）domains, Src homology 3（SH3） domains and Src homology 2（SH2） domain were conserved throughout the Vav2 gene family in vertebrates during gene evolution. Relative quantitative real-time PCR analysis showed that the LjVav2 was distributed in the heart, kidney, supraneural myeloid body, liver, gill and lymphocyte-like cells. The LjVav2 was found to be expressed in these tissues, and the level of which was upregulated in lymphocyte-like cells after the animal was stimulated with LPS. These results indicated that the Lj-Vav2 might be involved in the immune response of lymphocyte-like cells in lamprey. Meanwhile, our findings provided a foundation for further investigation of the function of Lj-Vav2 in the primary vertebrate.
基金supported by the National Natural Science Foundation of China(81970839,82271105,82330030,82121003,82101163)Sichuan Science and Technology Program(2023ZYD0059,2021YFS0369)+1 种基金Chengdu Science and Technology Program(2024-YF0501180-SN)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-032)。
文摘Primary open-angle glaucoma(POAG)is the leading cause of irreversible blindness worldwide,primarily due to the degeneration of retinal ganglion cells(RGCs).In this study,we reported vav guanine nucleotide exchange factor 2(VAV2)as a POAG-associated gene.Through whole exome sequencing(WES)of 398 Han Chinese POAG patients and 2,010 controls,we discovered nine rare VAV2 variants linked to POAG(P_burden=1.40×10^(-6)).Functional analyses revealed that these variants disrupted normal VAV2 protein function,leading to compromised cytoskeletal organization in human trabecular meshwork cells and impaired axonal growth in the 661W cell line.In vivo,Vav2 knockout mice exhibited key POAG features,including increased intraocular pressure(IOP),abnormal trabecular meshwork structure,reduced visual sensitivity,and RGC loss.This study also implicated VAV2 in the modulation of the Rho signaling pathway,which is essential for maintaining trabecular meshwork integrity and neuronal function.Taken together,this research identified VAV2 as a candidate gene for POAG and suggests VAV2 as a potential target for genetic screening of POAG diagnostics.
