AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia...AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.展开更多
Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regenera...Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regeneration. The sensory region of rat cochlea is difficult to transfect, thus new hair cells are rarely produced in situ in rat cochlear explants. After culturing rat cochleae in medium containing 10% fetal bovine serum, adenovirus successfully infected the sensory region as the width of the supporting cell area was significantly increased. Adenovirus encoding Atoh1 infected the sensory region and induced hair cell formation in situ. Combined application of the Notch inhibitor DAPT and Atoh1 increased the Atoh1 expression level and decreased hes1 and hes5 levels, further promoting hair cell generation. Our results demonstrate that DAPT enhances Atoh1 activity to promote hair cell regeneration in rat cochlear sensory epithelium in vitro.展开更多
More than 80%of all cases of deafness are related to the death or degeneration of cochlear hair cells and the associated spiral ganglion neurons,and a lack of regeneration of these cells leads to permanent hearing los...More than 80%of all cases of deafness are related to the death or degeneration of cochlear hair cells and the associated spiral ganglion neurons,and a lack of regeneration of these cells leads to permanent hearing loss.Therefore,the regeneration of lost hair cells is an important goal for the treatment of deafness.Atoh1 is a basic helix-loop-helix(bHLH)transcription factor that is critical in both the development and regeneration of cochlear hair cells.Atoh1 is transcriptionally regulated by several signaling pathways,including Notch and Wnt signalings.At the post-translational level,it is regulated through the ubiquitin-proteasome pathway.In vitro and in vivo studies have revealed that manipulation of these signaling pathways not only controls development,but also leads to the regeneration of cochlear hair cells after damage.Recent progress toward understanding the signaling networks involved in hair cell development and regeneration has led to the development of new strategies to replace lost hair cells.This review focuses on our current understanding of the signaling pathways that regulate Atoh1 in the cochlea.展开更多
Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are s...Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are still unclear.Here,we report that ATOH8-V1,a novel isoform of ATOH8,is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients.Forced expression of ATOH8-V1 dramatically enhances,while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines.Moreover,ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC,which in turn enhances the metastasis of breast cancer.Altogether,our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis,suggesting that AT0H8-V1 is a potential therapeutic target for treatment of metastatic cancers.展开更多
文摘AIM:To detect and segregate causative mutations in congenital families with optic nerve hypoplasia(ONH).M E T H O D S:Two unrel a ted consanguineous Pakistani families with severe ONH,showing features of micropthalmia,nystagmus,corneal opacity,and keratopathy were included.Genetic analysis was carried out by Target Panel Sequencing,and the nucleotide variant was confirmed by Sanger sequencing.In silico analyses were carried out to study the protein order-disorder functions and their effects on messenger ribonucleic acid(mRNA).RESULTS:Target panel sequencing revealed that the afflicted family members carried a novel frameshift mutation(NM_145178.4;c.91del G;p.Gly31Glyfs*55)that ensued in the conservation of an amino acid residue in the bHLH domain of ATOH7 protein.In silico studies predicted that the activity of the ATOH7 gene is probably affected by this mutation,which results in a shortened and nonfunctional protein.Three-dimensional structural analysis shows that DNA binding may be impacted by amino acid changes from non-polar to positively charged and vice versa(Arg42Pro and Pro18Arg),as well as from positively charged(Arg)to a small polar amino acid(Gly).CONCLUSION:A novel ATOH7 mutation is harmful.This study also emphasizes the potential effects of modified ATOH7 configurations on the stability and functionality of proteins.
基金supported by the National Natural Science Foundation of China,No.81420108010,81271084,81200740,81371093
文摘Atoh1 overexpression in cochlear epithelium induces new hair cell formation. Use of adenovirus-mediated Atoh1 overexpression has mainly focused on the rat lesser epithelial ridge and induces ectopic hair cell regeneration. The sensory region of rat cochlea is difficult to transfect, thus new hair cells are rarely produced in situ in rat cochlear explants. After culturing rat cochleae in medium containing 10% fetal bovine serum, adenovirus successfully infected the sensory region as the width of the supporting cell area was significantly increased. Adenovirus encoding Atoh1 infected the sensory region and induced hair cell formation in situ. Combined application of the Notch inhibitor DAPT and Atoh1 increased the Atoh1 expression level and decreased hes1 and hes5 levels, further promoting hair cell generation. Our results demonstrate that DAPT enhances Atoh1 activity to promote hair cell regeneration in rat cochlear sensory epithelium in vitro.
文摘More than 80%of all cases of deafness are related to the death or degeneration of cochlear hair cells and the associated spiral ganglion neurons,and a lack of regeneration of these cells leads to permanent hearing loss.Therefore,the regeneration of lost hair cells is an important goal for the treatment of deafness.Atoh1 is a basic helix-loop-helix(bHLH)transcription factor that is critical in both the development and regeneration of cochlear hair cells.Atoh1 is transcriptionally regulated by several signaling pathways,including Notch and Wnt signalings.At the post-translational level,it is regulated through the ubiquitin-proteasome pathway.In vitro and in vivo studies have revealed that manipulation of these signaling pathways not only controls development,but also leads to the regeneration of cochlear hair cells after damage.Recent progress toward understanding the signaling networks involved in hair cell development and regeneration has led to the development of new strategies to replace lost hair cells.This review focuses on our current understanding of the signaling pathways that regulate Atoh1 in the cochlea.
基金This work was supported by the National Science Foundation for Young Scientists of China(81702994)International S&T Cooperation Program of China(2015DFA30420)We thank Dr Ralph A.Reisfeld from the Scripps Research In stitute for his valuable suggestions and for proof-readi ng this manuscript.
文摘Metastases are the main cause of cancer-related mortality in breast cancer.Although significant progress has been made in the field of tumor metastasis,the exact molecular mechanisms involved in tumor metastasis are still unclear.Here,we report that ATOH8-V1,a novel isoform of ATOH8,is highly expressed in breast cancer and is a negative prognostic indicator of survival for patients.Forced expression of ATOH8-V1 dramatically enhances,while silencing of ATOH8-V1 decreases the metastasis of breast cancer cell lines.Moreover,ATOH8-V1 directly binds to the RhoC promoter and stimulates the expression of RhoC,which in turn enhances the metastasis of breast cancer.Altogether,our data demonstrate that ATOH8-V1 is a novel pro-metastatic factor that enhances cancer metastasis,suggesting that AT0H8-V1 is a potential therapeutic target for treatment of metastatic cancers.
