A key issue to be addressed in stem cell biology is the molecular signaling mechanism controlling embryonic stem （ES） cell pluripotency. Stem cell properties are dictated by specific transcription factors and epigen...A key issue to be addressed in stem cell biology is the molecular signaling mechanism controlling embryonic stem （ES） cell pluripotency. Stem cell properties are dictated by specific transcription factors and epigenetic processes such as DNA methylation and chromatin remodeling. Several cytokines/growth factors have been identified as critical ES cell regulators. However, there is a gap in our knowledge of the intracellular signaling pathways linking extracellular signals to transcriptional regulation in ES cells. This short review discusses the physiological role of Shp2, a cytoplasmic tyro- sine phosphatase, in the molecular switch governing ES cell self-renewal versus differentiation. Shp2 promotes ES cell differentiation, mainly through bi-directional modulation of Erk and Stat3 pathways. Deletion of Shp2 in mouse ES cells results in more efficient self-renewal. This observation provides the impetus to develop Shp2 inhibitors for maintenance and amplification of ES cells in culture.展开更多
Hearing impairment(HI)affects 1/1000 children and over 2%of the aged population.We have previously reported that mutations in the gene encoding gap junction protein connexin-31(Cx31)are associated with HI.The patholog...Hearing impairment(HI)affects 1/1000 children and over 2%of the aged population.We have previously reported that mutations in the gene encoding gap junction protein connexin-31(Cx31)are associated with HI.The pathological mechanism of the disease mutations remains unknown.Here,we show that expression of Cx31 in the mouse inner ear is developmentally regulated with a high level in adult inner hair cells and spiral ganglion neurons that are critical for the hearing process.In transfected cells,wild type Cx31 protein(Cx31wt)forms functional gap junction at cell-cell-contacts.In contrast,two HIassociated Cx31 mutants,Cx31R180X and Cx31E183K resided primarily in the ER and Golgi-like intracellular punctate structures,respectively,and failed to mediate lucifer yellow transfer.Expression of Cx31 mutants but not Cx31wt leads to upregulation of and increased association with the ER chaperone BiP indicating ER stress induction.Together,the HI-associated Cx31 mutants are impaired in trafficking,promote ER stress,and hence lose the ability to assemble functional gap junctions.The study reveals a potential pathological mechanism of HI-associated Cx31 mutations.展开更多
基金supported by grants from National Basic Research Program of China(2004CB518601, 2004CB518800)The National Natural Science Foundation of China (30730052, 30630062)~~
文摘A key issue to be addressed in stem cell biology is the molecular signaling mechanism controlling embryonic stem （ES） cell pluripotency. Stem cell properties are dictated by specific transcription factors and epigenetic processes such as DNA methylation and chromatin remodeling. Several cytokines/growth factors have been identified as critical ES cell regulators. However, there is a gap in our knowledge of the intracellular signaling pathways linking extracellular signals to transcriptional regulation in ES cells. This short review discusses the physiological role of Shp2, a cytoplasmic tyro- sine phosphatase, in the molecular switch governing ES cell self-renewal versus differentiation. Shp2 promotes ES cell differentiation, mainly through bi-directional modulation of Erk and Stat3 pathways. Deletion of Shp2 in mouse ES cells results in more efficient self-renewal. This observation provides the impetus to develop Shp2 inhibitors for maintenance and amplification of ES cells in culture.
基金supported by grants from the Chinese National Science Foundation(ZZ,KX,DLW)the NIH/NIDCD(ZZ).
文摘Hearing impairment(HI)affects 1/1000 children and over 2%of the aged population.We have previously reported that mutations in the gene encoding gap junction protein connexin-31(Cx31)are associated with HI.The pathological mechanism of the disease mutations remains unknown.Here,we show that expression of Cx31 in the mouse inner ear is developmentally regulated with a high level in adult inner hair cells and spiral ganglion neurons that are critical for the hearing process.In transfected cells,wild type Cx31 protein(Cx31wt)forms functional gap junction at cell-cell-contacts.In contrast,two HIassociated Cx31 mutants,Cx31R180X and Cx31E183K resided primarily in the ER and Golgi-like intracellular punctate structures,respectively,and failed to mediate lucifer yellow transfer.Expression of Cx31 mutants but not Cx31wt leads to upregulation of and increased association with the ER chaperone BiP indicating ER stress induction.Together,the HI-associated Cx31 mutants are impaired in trafficking,promote ER stress,and hence lose the ability to assemble functional gap junctions.The study reveals a potential pathological mechanism of HI-associated Cx31 mutations.
