Dataset Information

Role of bone morphogenetic proteins on cochlear hair cell formation: analyses of Noggin and Bmp2 mutant mice.

ABSTRACT: The mammalian organ of Corti of the inner ear is a highly sophisticated sensory end organ responsible for detecting sound. Noggin is a secreted glycoprotein, which antagonizes bone morphogenetic proteins 2 and 4 (Bmp2 and Bmp4). The lack of this antagonist causes increased rows of inner and outer hair cells in the organ of Corti. In mice, Bmp2 is expressed transiently in nascent cochlear hair cells. To investigate whether Noggin normally modulates the levels of Bmp2 for hair cell formation, we deleted Bmp2 in the cochlear hair cells using two cre strains, Foxg1(cre/+) and Gfi1(cre/+). Bmp2 conditional knockout cochleae generated using these two cre strains show normal hair cells. Furthermore, Gfi1(cre/+);Bmp2(lox/-) mice are viable and have largely normal hearing. The combined results of Noggin and Bmp2 mutants suggest that Noggin is likely to regulate other Bmps in the cochlea such as Bmp4.

SUBMITTER: Hwang CH

PROVIDER: S-EPMC5843465 | biostudies-literature | 2010 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Role of bone morphogenetic proteins on cochlear hair cell formation: analyses of Noggin and Bmp2 mutant mice.

Hwang Chan Ho CH Guo Dayong D Harris Marie A MA Howard Omar O Mishina Yuji Y Gan Lin L Harris Stephen E SE Wu Doris K DK

Developmental dynamics : an official publication of the American Association of Anatomists 20100201 2

The mammalian organ of Corti of the inner ear is a highly sophisticated sensory end organ responsible for detecting sound. Noggin is a secreted glycoprotein, which antagonizes bone morphogenetic proteins 2 and 4 (Bmp2 and Bmp4). The lack of this antagonist causes increased rows of inner and outer hair cells in the organ of Corti. In mice, Bmp2 is expressed transiently in nascent cochlear hair cells. To investigate whether Noggin normally modulates the levels of Bmp2 for hair cell formation, we d ...[more]

PMID: 20063299

Similar Datasets

Project description:The concentration, location, and timing of bone morphogenetic protein 2 (BMP2, HGNC:1069, GeneID: 650) gene expression must be precisely regulated. Abnormal BMP2 levels cause congenital anomalies and diseases involving the mesenchymal cells that differentiate into muscle, fat, cartilage, and bone. The molecules and conditions that influence BMP2 synthesis are diverse. Understandably, complex mechanisms control Bmp2 gene expression. This review includes a compilation of agents and conditions that can induce Bmp2. The currently known trans-regulatory factors and cis-regulatory elements that modulate Bmp2 expression are summarized and discussed. Bone morphogenetic protein 2 (BMP2, HGNC:1069, GeneID: 650) is a classical morphogen; a molecule that acts at a distance and whose concentration influences cell behavior. In mesenchymal cells, the concentration of BMP2 influences myogenesis, adipogenesis, chondrogenesis, and osteogenesis. Because the amount, timing, and location of BMP2 synthesis influence the allocation of cells to muscle, fat, cartilage, and bone, the mechanisms that regulate the Bmp2 gene are crucial. Key early mesodermal events that require precise Bmp2 regulation include heart specification and morphogenesis. Originally named for its osteoinductive properties, healing fractures requires BMP2. The human Bmp2 gene also has been linked to osteoporosis and osteoarthritis. In addition, all forms of pathological calcification in the vasculature and in cardiac valves involve the pro-osteogenic BMP2. The diverse tissues, mechanisms, and diseases influenced by BMP2 are too numerous to list here (see OMIM: 112261). However, in all BMP2-influenced pathologies, changes in the behavior and differentiation of pluripotent mesenchymal cells are a recurring theme. Consequently, much effort has been devoted to identifying the molecules and conditions that influence BMP2 synthesis and the complex mechanisms that control Bmp2 gene expression. This review begins with an overview of the Bmp2 gene's chromosomal neighborhood and then summarizes and evaluates known regulatory mechanisms and inducers.

Project description:Bone morphogenetic protein 2 (BMP2)-induced osteogenic differentiation has been shown to occur through the canonical Wnt/?catenin pathway, whereas factors promoting canonical Wnt signaling in cementoblasts inhibit cell differentiation and promote cell proliferation in vitro. The aim of this study was to investigate whether putative precursor cells of cementoblasts, dental follicle cells (murine SVF4 cells), when stimulated with BMP2, would exhibit changes in genes/proteins associated with the Wnt/?-catenin pathway.SVF4 cells were stimulated with BMP2, and the following assays were carried out: (i) Wnt/?-catenin pathway activation assessed by western blotting, ?-catenin/transcription factor (TCF) reporter assays and expression of the lymphoid enhancer-binding factor-1 (Lef1), transcription factor 7 (Tcf7), Wnt inhibitor factor 1 (Wif1) and Axin2 (Axin2) genes; and (ii) cementoblast/osteoblast differentiation assessed by mineralization in vitro, and by the mRNA levels of runt-related transcription factor 2 (Runx2), osterix (Osx), alkaline phosphatase (Alp), osteocalcin (Ocn) and bone sialoprotein (Bsp), determined by quantitative PCR after treatment with wingless-type MMTV integration site family, member 3A (WNT3A) and knockdown of ?-catenin.WNT3A induced ?-catenin nuclear translocation and up-regulated the transcriptional activity of a canonical Wnt-responsive reporter, suggesting that the Wnt/?-catenin pathway functions in SVF4 cells. Activation of Wnt signaling with WNT3A suppressed BMP2-mediated induction of cementoblast/osteoblast maturation of SVF4 cells. However, ?-catenin knockdown showed that the BMP2-induced expression of cementoblast/osteoblast differentiation markers requires endogenous ?-catenin. WNT3A down-regulated transcripts for Runx2, Alp and Ocn in SVF4 cells compared with untreated cells. In contrast, BMP2 induction of Bsp transcripts occurred independently of Wnt/?-catenin signaling.These data suggest that stabilization of ?-catenin by WNT3A inhibits BMP2-mediated induction of cementoblast/osteoblast differentiation in SVF4 cells, although BMP2 requires endogenous Wnt/?-catenin signaling to promote cell maturation.

Project description:Bone cancer pain is one of the most severe and intractable complications in patients suffering from primary or metastatic bone cancer and profoundly compromises the quality of life. Emerging evidence indicates that the dorsal root ganglion play an integral role in the modulation of pain hypersensitivity. However, the underlying molecular mechanisms during dorsal root ganglion-mediated bone cancer pain remain elusive. In this study, RNA-sequencing was used to detect the differentially expressed genes in dorsal root ganglion neurons of a rat bone cancer pain model established by intratibial inoculation of Walker 256 breast cancer cells. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that the differentially expressed genes (fold change?>?1.5; false discovery rate?<?0.05) were enriched in the bone morphogenetic protein (BMP) signaling pathway, transforming growth factor-? signaling pathway, and positive regulation of cartilage development. Importantly, serum deprivation-response protein ( Sdpr), hephaestin ( Heph), transthyretin ( Ttr), insulin receptor substrate 1 ( Irs1), connective tissue growth factor ( Ctgf?), and Bmp2 genes were associated with bone pain and degeneration. Of note, Bmp2, a pleiotropic and secreted molecule mediating pain and inflammation, was one of the most significantly upregulated genes in dorsal root ganglion neurons in this bone cancer pain model. Consistent with these data, upregulation of Bmp2 in the bone cancer pain model was validated by immunohistochemistry, real-time quantitative polymerase chain reaction, and western blotting. Importantly, intrathecal administration of siRNA significantly reduced Bmp2 transcription and ameliorated bone cancer pain in rat as shown by paw withdrawal mechanical threshold and spontaneous and movement-evoked pain-like behaviors. In conclusion, we have characterized the comprehensive gene expression profile of dorsal root ganglion from a bone cancer pain rat model by RNA-sequencing and identified Bmp2 as a potential therapeutic target for bone cancer pain treatment.

Dataset Information

Role of bone morphogenetic proteins on cochlear hair cell formation: analyses of Noggin and Bmp2 mutant mice.

Publications

Role of bone morphogenetic proteins on cochlear hair cell formation: analyses of Noggin and Bmp2 mutant mice.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets