Smaller inner ear sensory epithelia in Neurog1 null mice are related to earlier hair cell cycle exit

Matei, Veronica; Pauley, Sarah; Kaing, Sovann; Rowitch, David H.; Beisel, Kirk W.; Morris, Ken A.; Feng, Fan; Jones, Kevin R.; Lee, J.; Fritzsch, Bernd

doi:10.1002/dvdy.20551

Cited by 396 publications

(654 citation statements)

References 61 publications

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“…Because of the lack of antibodies that efficiently precipitate endogenous Gli proteins, we used antibodies against the FLAG epitope to isolate Gli1-bound chromatin from mice carrying a conditional FLAGtagged Gli1 transgene, Rosa Gli1-FLAG/Gli1-FLAG (22). Gli1-FLAG was produced in GNPs by breeding Rosa Gli1-FLAG/Gli1-FLAG animals to mice expressing Cre under the control of the Math1 promoter (24). This promoter is active in dividing GNPs and in MBs.…”

Section: Resultsmentioning

confidence: 99%

Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis

Lee

Ouyang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

112

101

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Many genes initially identified for their roles in cell fate determination or signaling during development can have a significant impact on tumorigenesis. In the developing cerebellum, Sonic hedgehog (Shh) stimulates the proliferation of granule neuron precursor cells (GNPs) by activating the Gli transcription factors. Inappropriate activation of Shh target genes results in unrestrained cell division and eventually medulloblastoma, the most common pediatric brain malignancy. We find dramatic differences in the gene networks that are directly driven by the Gli1 transcription factor in GNPs and medulloblastoma. Gli1 binding location analysis revealed hundreds of genomic loci bound by Gli1 in normal and cancer cells. Only one third of the genes bound by Gli1 in GNPs were also bound in tumor cells. Correlation with gene expression levels indicated that 116 genes were preferentially transcribed in tumors, whereas 132 genes were target genes in both GNPs and medulloblastoma. Quantitative PCR and in situ hybridization for some putative target genes support their direct regulation by Gli. The results indicate that transformation of normal GNPs into deadly tumor cells is accompanied by a distinct set of Gli-regulated genes and may provide candidates for targeted therapies.

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Section: Resultsmentioning

confidence: 99%

Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis

Lee

Ouyang³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

112

101

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“…The molecular mechanisms underlying the development of the sensory lineage and the patterning of the or-gan of Corti have been studied extensively (Adam et al, 1998;Haddon et al, 1998;Lewis et al, 1998;Lewis, 1998;Bermingham et al, 1999;Lanford et al, 1999Lanford et al, , 2000Morrison et al, 1999;Riley et al, 1999;Eddison et al, 2000;Zhang et al, 2000;Zine et al, 2000Zine et al, , 2001Tsai et al, 2001;Bryant et al, 2002;Chen et al, 2002;Fekete and Wu, 2002;Radde-Gallwitz et al, 2004;Woods et al, 2004;Daudet and Lewis, 2005;Kiernan et al, 2005a,b;Matei et al, 2005). In particular, two classes of basic helix-loop-helix (bHLH)-containing factors, namely the positively and negatively acting transcription factors, have been shown to play essential roles in the differentiation of sensory hair cells and the patterning of the sensory mosaic in the organ of Corti (Bermingham et al, 1999;Zine et al, 2000Zine et al, , 2001Chen et al, 2002;Woods et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…In particular, two classes of basic helix-loop-helix (bHLH)-containing factors, namely the positively and negatively acting transcription factors, have been shown to play essential roles in the differentiation of sensory hair cells and the patterning of the sensory mosaic in the organ of Corti (Bermingham et al, 1999;Zine et al, 2000Zine et al, , 2001Chen et al, 2002;Woods et al, 2004). Math1, a mouse homolog of the Drosophila proneural bHLH gene Atonal, also known as Atoh1 (Atonal homolog 1), is up-regulated within the sensory precursor domain of the cochlea around E13.5-E14.5 (Chen et al, 2002;Woods et al, 2004;Kiernan et al, 2005a;Matei et al, 2005). The onset of Math1 expression in the cochlea leads the differentiation gradient of hair cells (Chen et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…The onset of Math1 expression in the cochlea leads the differentiation gradient of hair cells (Chen et al, 2002). Although the precursor domain of the organ of Corti appears to still be specified in the absence of Math1 (Chen et al, 2002;Woods et al, 2004;Kiernan et al, 2005a;Matei et al, 2005), none of the examined hair cell markers is expressed, and Math1 is required for the differentiation of hair cells and the survival of the sensory lineage (Chen et al, 2002;Woods et al, 2004). In addition, introduction of Math1 to the cochlear epithelium leads to the expression of markers specific for hair cells and morphological differentiation of ectopic hair cells Shou et al, 2003;Kawamoto et al, 2003;Woods et al, 2004;Izumikawa et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

et al. 2006

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The basic helix-loop-helix (bHLH) gene Hes6 is known to promote neural differentiation in vitro. Here, we report the expression and functional studies of Hes6 in the inner ear. The expression of Hes6 appears to be parallel to that of Math1 (also known as Atoh1), a bHLH gene necessary and sufficient for hair cell differentiation. Hes6 is expressed initially in the presumptive hair cell precursors in the cochlea. Subsequently, the expression of Hes6 is restricted to morphologically differentiated hair cells. Similarly, the expression of Hes6 in the vestibule is in the hair cell lineage. Hes6 is dispensable for hair cell differentiation, and its expression in inner ear hair cells is abolished in the Math1-null animals. Furthermore, the introduction of Hes6 into the cochlea in vitro is not sufficient to promote sensory or neuronal differentiation. Therefore, Hes6 is downstream of Math1 and its expression in the inner ear delineates the sensory lineage. However, the role of Hes6 in the inner ear remains elusive.

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“…The neurotrophin-mediated conversion to progenitor cells had a more rapid time course that we found for EGF, IGF-1 and bFGF alone. The expression of proneural transcription factors, NeuroD and Ngn1, as well as neural and hair cell lineage markers, GATA3, Math1 and Brn3c, were also increased and the expression of Ngn1 and NeuroD, which select for a neural over a hair cell fate in the inner ear (Kim et al, 2001;Matei et al, 2005) were higher when NT-3 and BDNF were included in the differentiation medium. Other transcription factors expressed in the otic precursors during development, Zic2 and Pax6, were elevated in the progenitor cells relative to the MSCs, and Zic1 expression was not observed.…”

Section: Sensory Progenitors From Mesenchymal Stem Cellsmentioning

confidence: 99%

Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells

Jeon

Oshima

Heller

et al. 2007

Molecular and Cellular Neuroscience

108

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Stem cells have been demonstrated in the inner ear but they do not spontaneously divide to replace damaged sensory cells. Mesenchymal stem cells (MSC) from bone marrow have been reported to differentiate into multiple lineages including neurons, and we therefore asked whether MSCs could generate sensory cells. Overexpression of the prosensory transcription factor, Math1, in sensory epithelial precursor cells induced expression of myosin VIIa, espin, Brn3c, p27Kip, and jagged2, indicating differentiation to inner ear sensory cells. Some of the cells displayed F-actin positive protrusions in the morphology characteristic of hair cell stereociliary bundles. Hair cell markers were also induced by culture of mouse MSC-derived cells in contact with embryonic chick inner ear cells, and this induction was not due to a cell fusion event, because the chick hair cells could be identified with a chick-specific antibody and chick and mouse antigens were never found in the same cell.Stem cells resident in bone marrow are the source of blood cells, but in addition to these hematopoietic stem cells, the bone marrow contains mesenchymal stem cells (MSCs) that can differentiate into cell types of all three embryonic germ layers (Colter et al., 2000;Doyonnas et al., 2004;Herzog et al., 2003;Hess et al., 2003;Jiang et al., 2002;Pittenger et al., 1999). This has been demonstrated in vivo in studies that track transplanted bone marrow cells to specific tissues where they differentiate into the resident tissue type (Mezey et al., 2003;Weimann et al., 2003). Differentiation may occur in part due to cell fusion (Wang et al., 2003;Weimann et al., 2003) in which the bone marrow cell takes on the identity of the peripheral cell. Recent studies have documented ex vivo differentiation of bone marrow derived stem cells into muscle cells (Doyonnas et al., 2004), cartilage (Pittenger et al., 1999), insulin-producing cells (Hess et al., 2003), and neurons (Dezawa et al., 2004;Hermann et al., 2004;Jiang et al., 2003;Kicic et al., 2003), both in vitro and after injection of these cells in vivo. Many of these cells have been used for transplantation and are a © 2006 Elsevier Inc. All rights reserved.Corresponding author: Albert Edge Eaton-Peabody Laboratory Massachusetts Eye and Ear Infirmary 243 Charles Street Boston, MA 02114 Tel: (617) 573-4452 Fax: (617) 720-4408 albert_edge@meei.harvard.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptMol Cell Neurosci. Author manuscript; available in PMC 2011 July 14. (Satoh and Fekete, 2005), and by the effect on hair ce...

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Smaller inner ear sensory epithelia in Neurog1 null mice are related to earlier hair cell cycle exit

Cited by 396 publications

References 61 publications

Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis

Hedgehog pathway-regulated gene networks in cerebellum development and tumorigenesis

Basic helix–loop–helix gene Hes6 delineates the sensory hair cell lineage in the inner ear

Bone marrow mesenchymal stem cells are progenitors in vitro for inner ear hair cells

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