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Amita Arora - One of the best experts on this subject based on the ideXlab platform.

  • osbp related protein 2 orp2 unraveling its functions in Cellular lipid carbohydrate metabolism signaling and f actin regulation
    The Journal of Steroid Biochemistry and Molecular Biology, 2019
    Co-Authors: Vesa M Olkkonen, Annika Koponen, Amita Arora
    Abstract:

    Abstract Oxysterol-binding protein (OSBP)-related proteins (ORPs) constitute a family of intraCellular lipid-binding/transport proteins (LTPs) in eukaryotes. They typically have a modular structure comprising a lipid-binding domain and membrane targeting determinants, being thus suited for function at membrane contact sites. Among the mammalian ORPs, ORP2/OSBPL2 is the only member that only exists as a ‘short’ variant lacking a membrane-targeting pleckstrin homology domain. ORP2 is expressed ubiquitously and has been assigned a multitude of functions. Its OSBP-related domain binds cholesterol, oxysterols, and phosphoinositides, and its overexpression enhances Cellular cholesterol efflux. Consistently, the latest observations suggest a function of ORP2 in cholesterol transport to the plasma membrane (PM) in exchange for phosphatidylinositol 4,5-bisphosphate (PI4,5P2), with significant impacts on the concentrations of PM cholesterol and PI4,5P2. On the other hand, ORP2 localizes at the surface of cytoplasmic lipid droplets (LDs) and at endoplasmic-reticulum-LD contact sites, and its depletion modifies Cellular triglyceride (TG) metabolism. Study in an adrenocortical Cell line further suggested a function of ORP2 in the synthesis of steroid hormones. Our recent knock-out of ORP2 in human hepatoma Cells revealed its function in hepatoCellular PI3K/Akt signaling, glucose and triglyceride metabolism, as well as in actin cytoskeletal regulation, Cell adhesion, migration and proliferation. ORP2 was shown to interact physically with F-actin regulators such as DIAPH1, ARHGAP12, SEPT9 and MLC12, as well as with IQGAP1 and the Cdc37-Hsp90 chaperone complex controlling the activity of Akt. Interestingly, mutations in OSBPL2 encoding ORP2 are associated with autosomal dominant non-syndromic hearing loss, and the protein was found to localize in Cochlear Hair Cell stereocilia. The functions assigned to ORP2 suggest that this protein, in concert with other LTPs, controls the subCellular distribution of cholesterol in various Cell types and steroid hormone synthesis in adrenocortical Cells. However, it also impacts Cellular TG and carbohydrate metabolism and F-actin-dependent functions, revealing a bewildering spectrum of activities.

  • osbp related protein 2 orp2 unraveling its functions in Cellular lipid carbohydrate metabolism signaling and f actin regulation
    The Journal of Steroid Biochemistry and Molecular Biology, 2019
    Co-Authors: Vesa M Olkkonen, Annika Koponen, Amita Arora
    Abstract:

    Oxysterol-binding protein (OSBP)-related proteins (ORPs) constitute a family of intraCellular lipid-binding/transport proteins (LTPs) in eukaryotes. They typically have a modular structure comprising a lipid-binding domain and membrane targeting determinants, being thus suited for function at membrane contact sites. Among the mammalian ORPs, ORP2/OSBPL2 is the only member that only exists as a 'short' variant lacking a membrane-targeting pleckstrin homology domain. ORP2 is expressed ubiquitously and has been assigned a multitude of functions. Its OSBP-related domain binds cholesterol, oxysterols, and phosphoinositides, and its overexpression enhances Cellular cholesterol efflux. Consistently, the latest observations suggest a function of ORP2 in cholesterol transport to the plasma membrane (PM) in exchange for phosphatidylinositol 4,5-bisphosphate (PI4,5P2), with significant impacts on the concentrations of PM cholesterol and PI4,5P2. On the other hand, ORP2 localizes at the surface of cytoplasmic lipid droplets (LDs) and at endoplasmic-reticulum-LD contact sites, and its depletion modifies Cellular triglyceride (TG) metabolism. Study in an adrenocortical Cell line further suggested a function of ORP2 in the synthesis of steroid hormones. Our recent knock-out of ORP2 in human hepatoma Cells revealed its function in hepatoCellular PI3K/Akt signaling, glucose and triglyceride metabolism, as well as in actin cytoskeletal regulation, Cell adhesion, migration and proliferation. ORP2 was shown to interact physically with F-actin regulators such as DIAPH1, ARHGAP12, SEPT9 and MLC12, as well as with IQGAP1 and the Cdc37-Hsp90 chaperone complex controlling the activity of Akt. Interestingly, mutations in OSBPL2 encoding ORP2 are associated with autosomal dominant non-syndromic hearing loss, and the protein was found to localize in Cochlear Hair Cell stereocilia. The functions assigned to ORP2 suggest that this protein, in concert with other LTPs, controls the subCellular distribution of cholesterol in various Cell types and steroid hormone synthesis in adrenocortical Cells. However, it also impacts Cellular TG and carbohydrate metabolism and F-actin-dependent functions, revealing a bewildering spectrum of activities.

Vesa M Olkkonen - One of the best experts on this subject based on the ideXlab platform.

  • osbp related protein 2 orp2 unraveling its functions in Cellular lipid carbohydrate metabolism signaling and f actin regulation
    The Journal of Steroid Biochemistry and Molecular Biology, 2019
    Co-Authors: Vesa M Olkkonen, Annika Koponen, Amita Arora
    Abstract:

    Abstract Oxysterol-binding protein (OSBP)-related proteins (ORPs) constitute a family of intraCellular lipid-binding/transport proteins (LTPs) in eukaryotes. They typically have a modular structure comprising a lipid-binding domain and membrane targeting determinants, being thus suited for function at membrane contact sites. Among the mammalian ORPs, ORP2/OSBPL2 is the only member that only exists as a ‘short’ variant lacking a membrane-targeting pleckstrin homology domain. ORP2 is expressed ubiquitously and has been assigned a multitude of functions. Its OSBP-related domain binds cholesterol, oxysterols, and phosphoinositides, and its overexpression enhances Cellular cholesterol efflux. Consistently, the latest observations suggest a function of ORP2 in cholesterol transport to the plasma membrane (PM) in exchange for phosphatidylinositol 4,5-bisphosphate (PI4,5P2), with significant impacts on the concentrations of PM cholesterol and PI4,5P2. On the other hand, ORP2 localizes at the surface of cytoplasmic lipid droplets (LDs) and at endoplasmic-reticulum-LD contact sites, and its depletion modifies Cellular triglyceride (TG) metabolism. Study in an adrenocortical Cell line further suggested a function of ORP2 in the synthesis of steroid hormones. Our recent knock-out of ORP2 in human hepatoma Cells revealed its function in hepatoCellular PI3K/Akt signaling, glucose and triglyceride metabolism, as well as in actin cytoskeletal regulation, Cell adhesion, migration and proliferation. ORP2 was shown to interact physically with F-actin regulators such as DIAPH1, ARHGAP12, SEPT9 and MLC12, as well as with IQGAP1 and the Cdc37-Hsp90 chaperone complex controlling the activity of Akt. Interestingly, mutations in OSBPL2 encoding ORP2 are associated with autosomal dominant non-syndromic hearing loss, and the protein was found to localize in Cochlear Hair Cell stereocilia. The functions assigned to ORP2 suggest that this protein, in concert with other LTPs, controls the subCellular distribution of cholesterol in various Cell types and steroid hormone synthesis in adrenocortical Cells. However, it also impacts Cellular TG and carbohydrate metabolism and F-actin-dependent functions, revealing a bewildering spectrum of activities.

  • osbp related protein 2 orp2 unraveling its functions in Cellular lipid carbohydrate metabolism signaling and f actin regulation
    The Journal of Steroid Biochemistry and Molecular Biology, 2019
    Co-Authors: Vesa M Olkkonen, Annika Koponen, Amita Arora
    Abstract:

    Oxysterol-binding protein (OSBP)-related proteins (ORPs) constitute a family of intraCellular lipid-binding/transport proteins (LTPs) in eukaryotes. They typically have a modular structure comprising a lipid-binding domain and membrane targeting determinants, being thus suited for function at membrane contact sites. Among the mammalian ORPs, ORP2/OSBPL2 is the only member that only exists as a 'short' variant lacking a membrane-targeting pleckstrin homology domain. ORP2 is expressed ubiquitously and has been assigned a multitude of functions. Its OSBP-related domain binds cholesterol, oxysterols, and phosphoinositides, and its overexpression enhances Cellular cholesterol efflux. Consistently, the latest observations suggest a function of ORP2 in cholesterol transport to the plasma membrane (PM) in exchange for phosphatidylinositol 4,5-bisphosphate (PI4,5P2), with significant impacts on the concentrations of PM cholesterol and PI4,5P2. On the other hand, ORP2 localizes at the surface of cytoplasmic lipid droplets (LDs) and at endoplasmic-reticulum-LD contact sites, and its depletion modifies Cellular triglyceride (TG) metabolism. Study in an adrenocortical Cell line further suggested a function of ORP2 in the synthesis of steroid hormones. Our recent knock-out of ORP2 in human hepatoma Cells revealed its function in hepatoCellular PI3K/Akt signaling, glucose and triglyceride metabolism, as well as in actin cytoskeletal regulation, Cell adhesion, migration and proliferation. ORP2 was shown to interact physically with F-actin regulators such as DIAPH1, ARHGAP12, SEPT9 and MLC12, as well as with IQGAP1 and the Cdc37-Hsp90 chaperone complex controlling the activity of Akt. Interestingly, mutations in OSBPL2 encoding ORP2 are associated with autosomal dominant non-syndromic hearing loss, and the protein was found to localize in Cochlear Hair Cell stereocilia. The functions assigned to ORP2 suggest that this protein, in concert with other LTPs, controls the subCellular distribution of cholesterol in various Cell types and steroid hormone synthesis in adrenocortical Cells. However, it also impacts Cellular TG and carbohydrate metabolism and F-actin-dependent functions, revealing a bewildering spectrum of activities.

Shunbin Xu - One of the best experts on this subject based on the ideXlab platform.

  • the microrna 183 96 182 cluster is essential for stereociliary bundle formation and function of Cochlear sensory Hair Cells
    Scientific Reports, 2018
    Co-Authors: Ruishuang Geng, David N Furness, Chithra K Muraleedharan, Jinsheng Zhang, Alain Dabdoub, Shunbin Xu
    Abstract:

    The microRNA (miR)-183/96/182 cluster plays important roles in the development and functions of sensory organs, including the inner ear. Point-mutations in the seed sequence of miR-96 result in non-syndromic hearing loss in both mice and humans. However, the lack of a functionally null mutant has hampered the evaluation of the cluster’s physiological functions. Here we have characterized a loss-of-function mutant mouse model (miR-183CGT/GT), in which the miR-183/96/182 cluster gene is inactivated by a gene-trap (GT) construct. The homozygous mutant mice show profound congenital hearing loss with severe defects in Cochlear Hair Cell (HC) maturation, alignment, Hair bundle formation and the checkboard-like pattern of the Cochlear sensory epithelia. The stereociliary bundles retain an immature appearance throughout the cochlea at postnatal day (P) 3 and degenerate soon after. The organ of Corti of mutant newborn mice has no functional mechanoelectrical transduction. Several predicted target genes of the miR-183/96/182 cluster that are known to play important roles in HC development and function, including Clic5, Rdx, Ezr, Rac1, Myo1c, Pvrl3 and Sox2, are upregulated in the cochlea. These results suggest that the miR-183/96/182 cluster is essential for stereociliary bundle formation, morphogenesis and function of the Cochlear HCs.

Matthew W Kelley - One of the best experts on this subject based on the ideXlab platform.

  • characterizing adult Cochlear supporting Cell transcriptional diversity using single Cell rna seq validation in the adult mouse and translational implications for the adult human cochlea
    Frontiers in Molecular Neuroscience, 2020
    Co-Authors: Michael Hoa, Rafal Olszewski, Ian Taukulis, Alvin Detorres, Ivan A Lopez, Fred H Linthicum, Akira Ishiyama, Daniel Martin, Robert J Morell, Matthew W Kelley
    Abstract:

    Hearing loss is a problem that impacts a significant proportion of the adult population. Cochlear Hair Cell (HC) loss due to loud noise, chemotherapy and aging is the major underlying cause. A significant proportion of these individuals are dissatisfied with available treatment options which include hearing aids and Cochlear implants. An alternative approach to restore hearing would be to regenerate HCs. Such therapy would require a recapitulation of the complex architecture of the organ of Corti, necessitating regeneration of both mature HCs and supporting Cells (SCs). Transcriptional profiles of the mature Cell types in the cochlea are necessary to can provide a metric for eventual regeneration therapies. To assist in this effort, we sought to provide the first single-Cell characterization of the adult Cochlear SC transcriptome. We performed single-Cell RNA-Seq on FACS-purified adult Cochlear SCs from the LfngEGFP adult mouse, in which SCs express GFP. We demonstrate that adult Cochlear SCs are transcriptionally distinct from their perinatal counterparts. We establish Cell-type-specific adult Cochlear SC transcriptome profiles, and we validate these expression profiles through a combination of both fluorescent immunohistochemistry and in situ hybridization co-localization and quantitative polymerase chain reaction (qPCR) of adult Cochlear SCs. Furthermore, we demonstrate the relevance of these profiles to the adult human cochlea through immunofluorescent human temporal bone histopathology. Finally, we demonstrate Cell cycle regulator expression in adult SCs and perform pathway analyses to identify potential mechanisms for facilitating mitotic regeneration (Cell proliferation, differentiation, and eventually regeneration) in the adult mammalian cochlea. Our findings demonstrate the importance of characterizing mature as opposed to perinatal SCs.

  • characterizing adult Cochlear supporting Cell transcriptional diversity using single Cell rna seq validation in the adult mouse and translational implications for the adult human cochlea
    bioRxiv, 2019
    Co-Authors: Michael Hoa, Rafal Olszewski, Ian Taukulis, Alvin Detorres, Ivan A Lopez, Fred H Linthicum, Akira Ishiyama, Daniel Martin, Robert J Morell, Matthew W Kelley
    Abstract:

    Hearing loss is a problem that impacts a significant proportion of the adult population. Cochlear Hair Cell loss due to loud noise, chemotherapy and aging is the major underlying cause. A significant proportion of these individuals are dissatisfied with available treatment options which include hearing aids and Cochlear implants. An alternative approach to restore hearing would be to regenerate Hair Cells. Such therapy would require recapitulation of the complex architecture of the organ of Corti, necessitating regeneration of both mature Hair Cells and supporting Cells. Transcriptional profiles of the mature Cell types in the cochlea are necessary to can provide a metric for eventual regeneration therapies. To assist in this effort, we sought to provide the first single-Cell characterization of the adult Cochlear supporting Cell transcriptome. We performed single-Cell RNA-Seq on FACS-purified adult Cochlear supporting Cells from the LfngEGFP adult mouse, in which supporting Cells express GFP. We demonstrate that adult Cochlear supporting Cells are transcriptionally distinct from their perinatal counterparts. We establish Cell type-specific adult Cochlear supporting Cell transcriptome profiles, and we validate these expression profiles through a combination of both fluorescent immunohistochemistry and in situ hybridization co-localization and qPCR of adult Cochlear supporting Cells. Furthermore, we demonstrate the relevance of these profiles to the adult human cochlea through immunofluorescent human temporal bone histopathology. Finally, we demonstrate Cell cycle regulator expression in adult supporting Cells and perform pathway analyses to identify potential mechanisms for facilitating mitotic regeneration (Cell proliferation, differentiation, and eventually regeneration) in the adult mammalian cochlea. Our findings demonstrate the importance of characterizing mature as opposed to perinatal supporting Cells.

Zakia Abdelhamed - One of the best experts on this subject based on the ideXlab platform.

  • The Meckel-Gruber Syndrome protein TMEM67 (meckelin) regulates basal body planar polarization and non-canonical Wnt signalling via Wnt5a and ROR2
    Cilia, 2015
    Co-Authors: Zakia Abdelhamed, Subaashini Natarajan, C. F. Inglehearn, Carmel Toomes, Colin A. Johnson, Daniel J. Jagger
    Abstract:

    Results: Tmem67 mutant phenotypes include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and Cochlear Hair Cell stereociliary bundle orientation and basal body/ kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the Hair bundle, suggesting aberrant basal body migration. TMEM67 (meckelin) is essential for phosphorylation of the noncanonical Wnt receptor ROR2 (receptor tyrosine kinaselike orphan receptor 2) upon Wnt5a stimulation. ROR2 interacts with the intraCellular C-terminal domain of TMEM67 and co-localizes with TMEM67 at the ciliary transition zone. The N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Tmem67 mutant embryonic lungs in ex vivo culture failed to respond to Wnt5a stimulation of epithelial morphogenesis. However, stimulating the non-canonical Wnt pathway downstream of the receptor by activating RhoA resulted in an elicited response and the rescue of lung hypoplasia phenotypes.

  • the meckel gruber syndrome protein tmem67 controls basal body positioning and epithelial branching morphogenesis in mice via the non canonical wnt pathway
    Disease Models & Mechanisms, 2015
    Co-Authors: Zakia Abdelhamed, Subaashini Natarajan, C. F. Inglehearn, Carmel Toomes, Colin A. Johnson, Gabrielle Wheway, Daniel J. Jagger
    Abstract:

    Ciliopathies are a group of developmental disorders that manifest with multi-organ anomalies. Mutations in TMEM67 (MKS3) cause a range of human ciliopathies, including Meckel-Gruber and Joubert syndromes. In this study we describe multi-organ developmental abnormalities in the Tmem67(tm1Dgen/H1) knockout mouse that closely resemble those seen in Wnt5a and Ror2 knockout mice. These include pulmonary hypoplasia, ventricular septal defects, shortening of the body longitudinal axis, limb abnormalities, and Cochlear Hair Cell stereociliary bundle orientation and basal body/kinocilium positioning defects. The basal body/kinocilium complex was often uncoupled from the Hair bundle, suggesting aberrant basal body migration, although planar Cell polarity and apical planar asymmetry in the organ of Corti were normal. TMEM67 (meckelin) is essential for phosphorylation of the non-canonical Wnt receptor ROR2 (receptor-tyrosine-kinase-like orphan receptor 2) upon stimulation with Wnt5a-conditioned medium. ROR2 also colocalises and interacts with TMEM67 at the ciliary transition zone. Additionally, the extraCellular N-terminal domain of TMEM67 preferentially binds to Wnt5a in an in vitro binding assay. Cultured lungs of Tmem67 mutant mice failed to respond to stimulation of epithelial branching morphogenesis by Wnt5a. Wnt5a also inhibited both the Shh and canonical Wnt/β-catenin signalling pathways in wild-type embryonic lung. Pulmonary hypoplasia phenotypes, including loss of correct epithelial branching morphogenesis and Cell polarity, were rescued by stimulating the non-canonical Wnt pathway downstream of the Wnt5a-TMEM67-ROR2 axis by activating RhoA. We propose that TMEM67 is a receptor that has a main role in non-canonical Wnt signalling, mediated by Wnt5a and ROR2, and normally represses Shh signalling. Downstream therapeutic targeting of the Wnt5a-TMEM67-ROR2 axis might, therefore, reduce or prevent pulmonary hypoplasia in ciliopathies and other congenital conditions.