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However, another Notch ligand, JAG1, is expressed early in the sensory patches prior to cell differentiation, indicating that there may be an earlier role for Notch signaling in sensory development in the ear.

Amy E Kiernan et al.

PLoS Genetics 2 (1), 01 Jan 2006

Citation: Kiernan AE, Xu J, Gridley T (2006) The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear.

Amy E Kiernan et al.

PLoS Genetics 2 (1), 01 Jan 2006

Discussion We have demonstrated that Notch signaling, mediated by the JAG1 ligand, is required early in development for the formation of the sensory regions of the ear.

Amy E Kiernan et al.

PLoS Genetics 2 (1), 01 Jan 2006

One possibility is that another Notch ligand is compensating for the loss of JAG1 function.

Amy E Kiernan et al.

PLoS Genetics 2 (1), 01 Jan 2006

539 566 Lewis J 1991 Rules for the production of sensory cells Ciba Found Symp 160 25 53 1752167 Adam J Myat A Le Roux I Eddison M Henrique D 1998 Cell fate choices and the expression of Notch, Delta and Serrate homologues in the chick inner ear: Parallels with Drosophila sense-organ development Development 125 4645 4654 9806914 Eddison M Le Roux I Lewis J 2000 Notch signaling in the development of the inner ear: Lessons from Drosophila Proc Natl Acad Sci U S A 97 11692 11699 11050197 Parks AL Huppert SS Muskavitch MA 1997 The dynamics of neurogenic signalling underlying bristle development in Drosophila melanogaster Mech Dev 63 61 74 9178257 Bray S 1998 Notch signalling in Drosophila: Three ways to use a pathway Semin Cell Dev Biol 9 591 597 10075488 Lai EC 2004 Notch signaling: Control of cell communication and cell fate Development 131 965 973 14973298 Haddon C Jiang YJ Smithers L Lewis J 1998 Delta-Notch signalling and the patterning of sensory cell differentiation in the zebrafish ear: Evidence from the mind bomb mutant Development 125 4637 4644 9806913 Lanford PJ Lan Y Jiang R Lindsell C Weinmaster G 1999 Notch signalling pathway mediates hair cell development in mammalian cochlea Nat Genet 21 289 292 10080181 Riley BB Chiang M Farmer L Heck R 1999 The deltaA gene of zebrafish mediates lateral inhibition of hair cells in the inner ear and is regulated by pax2.1 Development 126 5669 5678 10572043 Zhang N Martin GV Kelley MW Gridley T 2000 A mutation in the Lunatic fringe gene suppresses the effects of a Jagged2 mutation on inner hair cell development in the cochlea Curr Biol 10 659 662 10837254 Zine A Aubert A Qiu J Therianos S Guillemot F 2001 Hes1 and Hes5 activities are required for the normal development of the hair cells in the mammalian inner ear J Neurosci 21 4712 4720 11425898 Daudet N Lewis J 2005 Two contrasting roles for Notch activity in chick inner ear development: Specification of prosensory patches and lateral inhibition of hair-cell differentiation Development 132 541 551 15634704 Kiernan AE Cordes R Kopan R Gossler A Gridley T 2005 The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear Development 132 4353 4362 16141228 Fekete DM Muthukumar S Karagogeos D 1998 Hair cells and supporting cells share a common progenitor in the avian inner ear J Neurosci 18 7811 7821 9742150 Baron M 2003 An overview of the Notch signalling pathway Semin Cell Dev Biol 14 113 119 12651094 Gridley T 2003 Notch signaling and inherited disease syndromes Hum Mol Genet 12 (Spec No 1) R9 R13 12668592 Schweisguth F 2004 Notch signaling activity Curr Biol 14 R129 138 14986688 Morrison A Hodgetts C Gossler A Hrabe de Angelis M Lewis J 1999 Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear Mech Dev 84 169 172 10473135 Bermingham NA Hassan BA Price SD Vollrath MA Ben-Arie N 1999 Math1: An essential gene for the generation of inner ear hair cells Science 284 1837 1841 10364557 Chen P Johnson JE Zoghbi HY Segil N 2002 The role of Math1 in inner ear development: Uncoupling the establishment of the sensory primordium from hair cell fate determination Development 129 2495 2505 11973280 Zheng JL Gao WQ 2000 Overexpression of Math1 induces robust production of extra hair cells in postnatal rat inner ears Nat Neurosci 3 580 586 10816314 Woods C Montcouquiol M Kelley MW 2004 Math1 regulates development of the sensory epithelium in the mammalian cochlea Nat Neurosci 7 1310 1318 15543141 Kiernan AE Pelling AL Leung KK Tang AS Bell DM 2005 Sox2 is required for sensory organ development in the mammalian inner ear Nature 434 1031 1035 15846349 Buescher M Hing FS Chia W 2002 Formation of neuroblasts in the embryonic central nervous system of Drosophila melanogaster is controlled by SoxNeuro Development 129 4193 4203 12183372 Overton PM Meadows LA Urban J Russell S 2002 Evidence for differential and redundant function of the Sox genes Dichaete and SoxN during CNS development in Drosophila Development 129 4219 4228 12183374 Kiernan AE Ahituv N Fuchs H Balling R Avraham KB 2001 The Notch ligand Jagged1 is required for inner ear sensory development Proc Natl Acad Sci U S A 98 3873 3878 11259677 Tsai H Hardisty RE Rhodes C Kiernan AE Roby P 2001 The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti Hum Mol Genet 10 507 512 11181574 Hebert JM McConnell SK 2000 Targeting of cre to the Foxg1 (BF-1) locus mediates loxP recombination in the telencephalon and other developing head structures Dev Biol 222 296 306 10837119 Pirvola U Ylikoski J Trokovic R Hebert JM McConnell SK 2002 FGFR1 is required for the development of the auditory sensory epithelium Neuron 35 671 680 12194867 Tax FE Yeargers JJ Thomas JH 1994 Sequence of C. elegans lag-2 reveals a cell-signalling domain shared with Delta and Serrate of Drosophila Nature 368 150 154 8139658 Shimizu K Chiba S Kumano K Hosoya N Takahashi T 1999 Mouse jagged1 physically interacts with notch2 and other notch receptors.

Amy E Kiernan et al.

PLoS Genetics 2 (1), 01 Jan 2006

Assessment by quantitative methods J Biol Chem 274 32961 32969 10551863 de Vries WN Binns LT Fancher KS Dean J Moore R 2000 Expression of Cre recombinase in mouse oocytes: A means to study maternal effect genes Genesis 26 110 112 10686600 Xue Y Gao X Lindsell CE Norton CR Chang B 1999 Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1 Hum Mol Genet 8 723 730 10196361 Ruben RJ 1967 Development of the inner ear of the mouse: A autoradiographic study of terminal mitoses Acta Oto-laryngologica (Suppl 220) 1 44 6067797 Chen P Segil N 1999 p27(Kip1) links cell proliferation to morphogenesis in the developing organ of Corti Development 126 1581 1590 10079221 Montcouquiol M Rachel RA Lanford PJ Copeland NG Jenkins NA 2003 Identification of Vangl2 and Scrb1 as planar polarity genes in mammals Nature 423 173 177 12724779 Lu X Borchers AG Jolicoeur C Rayburn H Baker JC 2004 PTK7/CCK-4 is a novel regulator of planar cell polarity in vertebrates Nature 430 93 98 15229603 Curtin JA Quint E Tsipouri V Arkell RM Cattanach B 2003 Mutation of Celsr1 disrupts planar polarity of inner ear hair cells and causes severe neural tube defects in the mouse Curr Biol 13 1129 1133 12842012 Wang J Mark S Zhang X Qian D Yoo SJ 2005 Regulation of polarized extension and planar cell polarity in the cochlea by the vertebrate PCP pathway Nat Genet 37 980 985 16116426 Yoon K Gaiano N 2005 Notch signaling in the mammalian central nervous system: Insights from mouse mutants Nat Neurosci 8 709 715 15917835 Gaiano N Fishell G 2002 The role of notch in promoting glial and neural stem cell fates Annu Rev Neurosci 25 471 490 12052917 Fre S Huyghe M Mourikis P Robine S Louvard D 2005 Notch signals control the fate of immature progenitor cells in the intestine Nature 435 964 968 15959516 van Es JH van Gijn ME Riccio O van den Born M Vooijs M 2005 Notch/gamma-secretase inhibition turns proliferative cells in intestinal crypts and adenomas into goblet cells Nature 435 959 963 15959515 Radtke F Clevers H 2005 Self-renewal and cancer of the gut: Two sides of a coin Science 307 1904 1909 15790842 Hitoshi S Alexson T Tropepe V Donoviel D Elia AJ 2002 Notch pathway molecules are essential for the maintenance, but not the generation, of mammalian neural stem cells Genes Dev 16 846 858 11937492 Ohtsuka T Sakamoto M Guillemot F Kageyama R 2001 Roles of the basic helix-loop-helix genes Hes1 and Hes5 in expansion of neural stem cells of the developing brain J Biol Chem 276 30467 30474 11399758 Gaiano N Nye JS Fishell G 2000 Radial glial identity is promoted by Notch1 signaling in the murine forebrain Neuron 26 395 404 10839358 Yoon K Nery S Rutlin ML Radtke F Fishell G 2004 Fibroblast growth factor receptor signaling promotes radial glial identity and interacts with Notch1 signaling in telencephalic progenitors J Neurosci 24 9497 9506 15509736 Anthony TE Klein C Fishell G Heintz N 2004 Radial glia serve as neuronal progenitors in all regions of the central nervous system Neuron 41 881 890 15046721 Ever L Gaiano N 2005 Radial “glial” progenitors: Neurogenesis and signaling Curr Opin Neurobiol 15 29 33 15721741 Stevens CB Davies AL Battista S Lewis JH Fekete DM 2003 Forced activation of Wnt signaling alters morphogenesis and sensory organ identity in the chicken inner ear Dev Biol 261 149 164 12941626 Hayward P Brennan K Sanders P Balayo T DasGupta R 2005 Notch modulates Wnt signalling by associating with Armadillo/beta-catenin and regulating its transcriptional activity Development 132 1819 1830 15772135 Arias AM 2002 New alleles of Notch draw a blueprint for multifunctionality Trends Genet 18 168 170 11932008 Devgan V Mammucari C Millar SE Brisken C Dotto GP 2005 p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation Genes Dev 19 1485 1495 15964998 Kubo F Takeichi M Nakagawa S 2005 Wnt2b inhibits differentiation of retinal progenitor cells in the absence of Notch activity by downregulating the expression of proneural genes Development 132 2759 2770 15901663 Morsli H Choo D Ryan A Johnson R Wu DK 1998 Development of the mouse inner ear and origin of its sensory organs J Neurosci 18 3327 3335 9547240 Chang W ten Dijke P Wu DK 2002 BMP pathways are involved in otic capsule formation and epithelial-mesenchymal signaling in the developing chicken inner ear Dev Biol 251 380 394 12435365 Cole LK Le Roux I Nunes F Laufer E Lewis J 2000 Sensory organ generation in the chicken inner ear: Contributions of bone morphogenetic protein 4, serrate1, and lunatic fringe J Comp Neurol 424 509 520 10906716 Chang W Brigande JV Fekete DM Wu DK 2004 The development of semicircular canals in the inner ear: Role of FGFs in sensory cristae Development 131 4201 4211 15280215 Pauley S Wright TJ Pirvola U Ornitz D Beisel K 2003 Expression and function of FGF10 in mammalian inner ear development Dev Dyn 227 203 215 12761848 Kawamoto K Ishimoto S Minoda R Brough DE Raphael Y 2003 Math1 gene transfer generates new cochlear hair cells in mature guinea pigs in vivo J Neurosci 23 4395 4400 12805278 Swiatek PJ Lindsell CE del Amo FF Weinmaster G Gridley T 1994 Notch1 is essential for postimplantation development in mice Genes Dev 8 707 719 7926761 Kiernan AE Zalzman M Fuchs H Hrabe de Angelis M Balling R 1999 Tailchaser (Tlc): A new mouse mutation affecting hair bundle differentiation and hair cell survival J Neurocytol 28 969 985 10900098 Jiang R Lan Y Norton CR Sundberg JP Gridley T 1998 The Slug gene is not essential for mesoderm or neural crest development in mice Dev Biol 198 277 285 9659933 Stern CD 1998 Detection of multiple gene products simultaneously by in situ hybridization and immunohistochemistry in whole mounts of avian embryos Curr Top Dev Biol 36 223 243 9342531 Rau A Legan PK Richardson GP 1999 Tectorin mRNA expression is spatially and temporally restricted during mouse inner ear development J Comp Neurol 405 271 280 10023815 Author contributions.

Amy E Kiernan et al.

PLoS Genetics 2 (1), 01 Jan 2006

Results To understand the role of auxilin in Notch ligand endocytosis, we have analyzed several point mutations affecting specific domains of dAux.

Vasundhara Kandachar et al.

BMC Developmental Biology 8 (7), 08 May 2008

In support of the genetic evidences, the level of Delta appears elevated in dAux deficient cells, suggesting that the endocytosis of Notch ligand is disrupted.

Vasundhara Kandachar et al.

BMC Developmental Biology 8 (7), 08 May 2008

Our data suggest that dAux mutations inhibit Notch ligand internalization at an early step during clathrin-mediated endocytosis, before the disassembly of clathrin-coated vesicles.

Vasundhara Kandachar et al.

BMC Developmental Biology 8 (7), 08 May 2008

Together, our observations argue that ligand endocytosis is critical for Notch signaling and auxilin participates in Notch signaling by facilitating ligand internalization.

Vasundhara Kandachar et al.

BMC Developmental Biology 8 (7), 08 May 2008

Initially, the identification of auxilin as a component of the Drosophila Notch pathway suggests that, to activate Notch, ligand endocytosis needs to proceed past the step of clathrin cage disassembly.

Vasundhara Kandachar et al.

BMC Developmental Biology 8 (7), 08 May 2008

These effects of GSI were also associated with increased expression of the Notch ligand Delta1 in T EFF cells.

Masakazu Okamoto et al.

The Journal of Experimental Medicine 205 (5), 12 May 2008

These results demonstrate a role for Notch in skewing the T cell response from a T helper (Th)2 to a Th1 phenotype as a consequence of the inhibition of Notch receptor activation and the up-regulation of the Notch ligand Delta1.

Masakazu Okamoto et al.

The Journal of Experimental Medicine 205 (5), 12 May 2008

Further, we showed that Delta1, a Notch ligand, is an effective inhibitor of allergen-induced AHR.

Masakazu Okamoto et al.

The Journal of Experimental Medicine 205 (5), 12 May 2008

Expression of Delta1 in T EFF cells from CD8 −/− recipients of GSI-T EFF cells or DMSO-T EFF cells To determine if Notch ligand expression was involved in the response of the transferred cells, CD8 + T EFF cells were isolated from the lungs of secondary challenged CD8 −/− recipients of either GSI-T EFF cells or DMSO-T EFF cells and analyzed by real-time PCR.

Masakazu Okamoto et al.

The Journal of Experimental Medicine 205 (5), 12 May 2008

Real-time PCR analysis of Notch ligand expression in T EFF cells.

Masakazu Okamoto et al.

The Journal of Experimental Medicine 205 (5), 12 May 2008

Notch1 primers amplify within the NotchIC and detect both endogenous and exogenous transcripts. (F) R26NotchIC cells (NotchIC) or parental 46C cells (control) cultured under monolayer differentiation conditions and stained for cytokeratin 8, a marker of nonneural differentiation (red) and counterstained with DAPI (blue) Figure 7 Notch Promotes Neural Differentiation of Human ES Cells (A–I) Human ES cells plated on OP9 feeder cells expressing either GFP only (OP9 EV) or the Notch ligand Delta1 (OP9 Dl1) with γ-secretase inhibitor where indicated (“+inhibitor”) were cultured for 7 d and stained for markers as indicated. (A) Higher magnification picture to indicate the cell morphology: the OP9-Dl1 feeders are green and the dotted line demarcates hES cells adjacent to the feeders that have adopted a neural morphology, while cells more distant from the feeders retain an ES-like morphology.

Sally Lowell et al.

PLoS Biology 4 (5), 01 May 2006

In contrast, mice treated with a Notch ligand Jagged peptide showed significantly enhanced wound healing compared to controls.

Srinivasulu Chigurupati et al.

PLoS ONE 2 (11), 14 Nov 2007

It was shown that mice lacking Notch [10] or the Notch ligand Jagged-1 [11] die during embryonic development as a result of vascular plexus remodeling defects.

Srinivasulu Chigurupati et al.

PLoS ONE 2 (11), 14 Nov 2007

In the present study we employed Notch antisense transgenic mice (NAS), γ-secretase enzyme inhibitors and the Notch ligand Jagged-1 to elucidate the role of Notch signaling in wound healing.

Srinivasulu Chigurupati et al.

PLoS ONE 2 (11), 14 Nov 2007

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