The Candidate Splicing Factor Sfswap Regulates Growth and Patterning of Inner Ear Sensory Organs


The Notch signaling pathway is thought to regulate multiple stages of inner ear development. Mutations in the Notch signaling pathway cause disruptions in the number and arrangement of hair cells and supporting cells in sensory regions of the ear. In this study we identify an insertional mutation in the mouse Sfswap gene, a putative splicing factor, that results in mice with vestibular and cochlear defects that are consistent with disrupted Notch signaling. Homozygous Sfswap mutants display hyperactivity and circling behavior consistent with vestibular defects, and significantly impaired hearing. The cochlea of newborn Sfswap mutant mice shows a significant reduction in outer hair cells and supporting cells and ectopic inner hair cells. This phenotype most closely resembles that seen in hypomorphic alleles of the Notch ligand Jagged1 (Jag1). We show that Jag1; Sfswap compound mutants have inner ear defects that are more severe than expected from simple additive effects of the single mutants, indicating a genetic interaction between Sfswap and Jag1. In addition, expression of genes involved in Notch signaling in the inner ear are reduced in Sfswap mutants. There is increased interest in how splicing affects inner ear development and function. Our work is one of the first studies to suggest that a putative splicing factor has specific effects on Notch signaling pathway members and inner ear development.


Vyšlo v časopise: The Candidate Splicing Factor Sfswap Regulates Growth and Patterning of Inner Ear Sensory Organs. PLoS Genet 10(1): e32767. doi:10.1371/journal.pgen.1004055
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1004055

Souhrn

The Notch signaling pathway is thought to regulate multiple stages of inner ear development. Mutations in the Notch signaling pathway cause disruptions in the number and arrangement of hair cells and supporting cells in sensory regions of the ear. In this study we identify an insertional mutation in the mouse Sfswap gene, a putative splicing factor, that results in mice with vestibular and cochlear defects that are consistent with disrupted Notch signaling. Homozygous Sfswap mutants display hyperactivity and circling behavior consistent with vestibular defects, and significantly impaired hearing. The cochlea of newborn Sfswap mutant mice shows a significant reduction in outer hair cells and supporting cells and ectopic inner hair cells. This phenotype most closely resembles that seen in hypomorphic alleles of the Notch ligand Jagged1 (Jag1). We show that Jag1; Sfswap compound mutants have inner ear defects that are more severe than expected from simple additive effects of the single mutants, indicating a genetic interaction between Sfswap and Jag1. In addition, expression of genes involved in Notch signaling in the inner ear are reduced in Sfswap mutants. There is increased interest in how splicing affects inner ear development and function. Our work is one of the first studies to suggest that a putative splicing factor has specific effects on Notch signaling pathway members and inner ear development.


Zdroje

1. LewisAK, FrantzGD, CarpenterDA, de SauvageFJ, GaoWQ (1998) Distinct expression patterns of notch family receptors and ligands during development of the mammalian inner ear. Mech Dev 78: 159–163.

2. MurataJ, TokunagaA, OkanoH, KuboT (2006) Mapping of notch activation during cochlear development in mice: implications for determination of prosensory domain and cell fate diversification. J Comp Neurol 497: 502–518.

3. MorrisonA, HodgettsC, GosslerA, Hrabe de AngelisM, LewisJ (1999) Expression of Delta1 and Serrate1 (Jagged1) in the mouse inner ear. Mech Dev 84: 169–172.

4. HartmanBH, HayashiT, NelsonBR, Bermingham-McDonoghO, RehTA (2007) Dll3 is expressed in developing hair cells in the mammalian cochlea. Dev Dyn 236: 2875–2883.

5. KiernanAE, CordesR, KopanR, GosslerA, GridleyT (2005) The Notch ligands DLL1 and JAG2 act synergistically to regulate hair cell development in the mammalian inner ear. Development 132: 4353–4362.

6. BrookerR, HozumiK, LewisJ (2006) Notch ligands with contrasting functions: Jagged1 and Delta1 in the mouse inner ear. Development 133: 1277–1286.

7. LanfordPJ, LanY, JiangR, LindsellC, WeinmasterG, et al. (1999) Notch signalling pathway mediates hair cell development in mammalian cochlea. Nat Genet 21: 289–292.

8. ZhangN, MartinGV, KelleyMW, GridleyT (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.

9. DoetzlhoferA, BaschML, OhyamaT, GesslerM, GrovesAK, et al. (2009) Hey2 regulation by FGF provides a Notch-independent mechanism for maintaining pillar cell fate in the organ of Corti. Dev Cell 16: 58–69.

10. TateyaT, ImayoshiI, TateyaI, ItoJ, KageyamaR (2011) Cooperative functions of Hes/Hey genes in auditory hair cell and supporting cell development. Dev Biol 352: 329–340.

11. LiS, MarkS, Radde-GallwitzK, SchlisnerR, ChinMT, et al. (2008) Hey2 functions in parallel with Hes1 and Hes5 for mammalian auditory sensory organ development. BMC Dev Biol 8: 20.

12. OhyamaT, BaschML, MishinaY, LyonsKM, SegilN, et al. (2010) BMP signaling is necessary for patterning the sensory and nonsensory regions of the developing mammalian cochlea. J Neurosci 30: 15044–15051.

13. KiernanAE, XuJ, GridleyT (2006) The Notch ligand JAG1 is required for sensory progenitor development in the mammalian inner ear. PLoS Genet 2: e4.

14. KiernanAE, AhituvN, FuchsH, BallingR, AvrahamKB, et al. (2001) The Notch ligand Jagged1 is required for inner ear sensory development. Proc Natl Acad Sci U S A 98: 3873–3878.

15. TsaiH, HardistyRE, RhodesC, KiernanAE, RobyP, et al. (2001) The mouse slalom mutant demonstrates a role for Jagged1 in neuroepithelial patterning in the organ of Corti. Hum Mol Genet 10: 507–512.

16. GreenMM (1959) Spatial and functional properties of pseudo-alleles at the white locus in Drosophila melanogaster. Heredity 303–315.

17. TwyffelsL, GueydanC, KruysV (2011) Shuttling SR proteins: more than splicing factors. FEBS J 278: 3246–3255.

18. ZacharZ, ChouTB, BinghamPM (1987) Evidence that a regulatory gene autoregulates splicing of its transcript. EMBO J 6: 4105–4111.

19. ZacharZ, ChouTB, KramerJ, MimsIP, BinghamPM (1994) Analysis of autoregulation at the level of pre-mRNA splicing of the suppressor-of-white-apricot gene in Drosophila. Genetics 137: 139–150.

20. RutledgeBJ, MortinMA, SchwarzE, Thierry-MiegD, MeselsonM (1988) Genetic interactions of modifier genes and modifiable alleles in Drosophila melanogaster. Genetics 119: 391–397.

21. SarkissianM, WinneA, LafyatisR (1996) The mammalian homolog of suppressor-of-white-apricot regulates alternative mRNA splicing of CD45 exon 4 and fibronectin IIICS. J Biol Chem 271: 31106–31114.

22. DenhezF, LafyatisR (1994) Conservation of regulated alternative splicing and identification of functional domains in vertebrate homologs to the Drosophila splicing regulator, suppressor-of-white-apricot. J Biol Chem 269: 16170–16179.

23. LemaireR, WinneA, SarkissianM, LafyatisR (1999) SF2 and SRp55 regulation of CD45 exon 4 skipping during T cell activation. Eur J Immunol 29: 823–837.

24. MountSM, GreenMM, RubinGM (1988) Partial revertants of the transposable element-associated suppressible allele white-apricot in Drosophila melanogaster: structures and responsiveness to genetic modifiers. Genetics 118: 221–234.

25. Overbeek PA (2002) Factors affecting transgenic animal production; Pinkert C, editor. New York, NY: Elsevier Science.

26. Hardisty-HughesRE, ParkerA, BrownSD (2010) A hearing and vestibular phenotyping pipeline to identify mouse mutants with hearing impairment. Nat Protoc 5: 177–190.

27. SalviRJ, DingD, WangJ, JiangHY (2000) A review of the effects of selective inner hair cell lesions on distortion product otoacoustic emissions, cochlear function and auditory evoked potentials. Noise Health 2: 9–26.

28. PaylorR, CrawleyJN (1997) Inbred strain differences in prepulse inhibition of the mouse startle response. Psychopharmacology (Berl) 132: 169–180.

29. Bermingham-McDonoghO, OesterleEC, StoneJS, HumeCR, HuynhHM, et al. (2006) Expression of Prox1 during mouse cochlear development. J Comp Neurol 496: 172–186.

30. MorsliH, ChooD, RyanA, JohnsonR, WuDK (1998) Development of the mouse inner ear and origin of its sensory organs. J Neurosci 18: 3327–3335.

31. MeyersJR, MacDonaldRB, DugganA, LenziD, StandaertDG, et al. (2003) Lighting up the senses: FM1-43 loading of sensory cells through nonselective ion channels. J Neurosci 23: 4054–4065.

32. PanW, JinY, StangerB, KiernanAE (2010) Notch signaling is required for the generation of hair cells and supporting cells in the mammalian inner ear. Proc Natl Acad Sci U S A 107: 15798–15803.

33. KiernanAE, LiR, HawesNL, ChurchillGA, GridleyT (2007) Genetic background modifies inner ear and eye phenotypes of jag1 heterozygous mice. Genetics 177: 307–311.

34. ChangW, LinZ, KulessaH, HebertJ, HoganBL, et al. (2008) Bmp4 is essential for the formation of the vestibular apparatus that detects angular head movements. PLoS Genet 4: e1000050.

35. KoutelouE, SatoS, Tomomori-SatoC, FlorensL, SwansonSK, et al. (2008) Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1. J Biol Chem 283: 3846–3853.

36. McGillMA, DhoSE, WeinmasterG, McGladeCJ (2009) Numb regulates post-endocytic trafficking and degradation of Notch1. J Biol Chem 284: 26427–26438.

37. McGillMA, McGladeCJ (2003) Mammalian numb proteins promote Notch1 receptor ubiquitination and degradation of the Notch1 intracellular domain. J Biol Chem 278: 23196–23203.

38. GaoZ, ChiFL, HuangYB, YangJM, CongN, et al. (2011) Expression of Numb and Numb-like in the development of mammalian auditory sensory epithelium. Neuroreport 22: 49–54.

39. NamY, SlizP, SongL, AsterJC, BlacklowSC (2006) Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes. Cell 124: 973–983.

40. FukamiM, WadaY, OkadaM, KatoF, KatsumataN, et al. (2008) Mastermind-like domain-containing 1 (MAMLD1 or CXorf6) transactivates the Hes3 promoter, augments testosterone production, and contains the SF1 target sequence. J Biol Chem 283: 5525–5532.

41. WuL, SunT, KobayashiK, GaoP, GriffinJD (2002) Identification of a family of mastermind-like transcriptional coactivators for mammalian notch receptors. Mol Cell Biol 22: 7688–7700.

42. PirrottaV, BrocklC (1984) Transcription of the Drosophila white locus and some of its mutants. EMBO J 3: 563–568.

43. LevisR, O'HareK, RubinGM (1984) Effects of transposable element insertions on RNA encoded by the white gene of Drosophila. Cell 38: 471–481.

44. ZacharZ, DavisonD, GarzaD, BinghamPM (1985) A detailed developmental and structural study of the transcriptional effects of insertion of the Copia transposon into the white locus of Drosophila melanogaster. Genetics 111: 495–515.

45. BlantonSH, LiangCY, CaiMW, PandyaA, DuLL, et al. (2002) A novel locus for autosomal dominant non-syndromic deafness (DFNA41) maps to chromosome 12q24-qter. J Med Genet 39: 567–570.

46. ChenQ, ChuH, WuX, CuiY, ChenJ, et al. (2011) The expression of plasma membrane Ca(2+)-ATPase isoform 2 and its splice variants at sites A and C in the neonatal rat cochlea. Int J Pediatr Otorhinolaryngol 75: 196–201.

47. BeiselKW, Rocha-SanchezSM, MorrisKA, NieL, FengF, et al. (2005) Differential expression of KCNQ4 in inner hair cells and sensory neurons is the basis of progressive high-frequency hearing loss. J Neurosci 25: 9285–9293.

48. Rocha-SanchezSM, MorrisKA, KacharB, NicholsD, FritzschB, et al. (2007) Developmental expression of Kcnq4 in vestibular neurons and neurosensory epithelia. Brain Res 1139: 117–125.

49. ShenY, YuD, HielH, LiaoP, YueDT, et al. (2006) Alternative splicing of the Ca(v)1.3 channel IQ domain, a molecular switch for Ca2+-dependent inactivation within auditory hair cells. J Neurosci 26: 10690–10699.

50. RamanathanK, MichaelTH, JiangGJ, HielH, FuchsPA (1999) A molecular mechanism for electrical tuning of cochlear hair cells. Science 283: 215–217.

51. LangerP, GrunderS, RuschA (2003) Expression of Ca2+-activated BK channel mRNA and its splice variants in the rat cochlea. J Comp Neurol 455: 198–209.

52. SakaiY, HarveyM, SokolowskiB (2011) Identification and quantification of full-length BK channel variants in the developing mouse cochlea. J Neurosci Res 89: 1747–1760.

53. HousleyGD, KanjhanR, RaybouldNP, GreenwoodD, SalihSG, et al. (1999) Expression of the P2X(2) receptor subunit of the ATP-gated ion channel in the cochlea: implications for sound transduction and auditory neurotransmission. J Neurosci 19: 8377–8388.

54. HillJK, WilliamsDE, LeMasurierM, DumontRA, StrehlerEE, et al. (2006) Splice-site A choice targets plasma-membrane Ca2+-ATPase isoform 2 to hair bundles. J Neurosci 26: 6172–6180.

55. GratiM, AggarwalN, StrehlerEE, WentholdRJ (2006) Molecular determinants for differential membrane trafficking of PMCA1 and PMCA2 in mammalian hair cells. J Cell Sci 119: 2995–3007.

56. FicarellaR, Di LevaF, BortolozziM, OrtolanoS, DonaudyF, et al. (2007) A functional study of plasma-membrane calcium-pump isoform 2 mutants causing digenic deafness. Proc Natl Acad Sci U S A 104: 1516–1521.

57. XuT, NieL, ZhangY, MoJ, FengW, et al. (2007) Roles of alternative splicing in the functional properties of inner ear-specific KCNQ4 channels. J Biol Chem 282: 23899–23909.

58. ChenC, ParkerMS, BarnesAP, DeiningerP, BobbinRP (2000) Functional expression of three P2X(2) receptor splice variants from guinea pig cochlea. J Neurophysiol 83: 1502–1509.

59. BrandleU, SpielmannsP, OsterothR, SimJ, SurprenantA, et al. (1997) Desensitization of the P2X(2) receptor controlled by alternative splicing. FEBS Lett 404: 294–298.

60. LuikartBW, NefS, ShipmanT, ParadaLF (2003) In vivo role of truncated trkb receptors during sensory ganglion neurogenesis. Neuroscience 117: 847–858.

61. NakanoY, JahanI, BondeG, SunX, HildebrandMS, et al. (2012) A mutation in the Srrm4 gene causes alternative splicing defects and deafness in the Bronx waltzer mouse. PLoS Genet 8: e1002966.

62. WebbSW, GrilletN, AndradeLR, XiongW, SwarthoutL, et al. (2011) Regulation of PCDH15 function in mechanosensory hair cells by alternative splicing of the cytoplasmic domain. Development 138: 1607–1617.

63. OuyangXM, XiaXJ, VerpyE, DuLL, PandyaA, et al. (2002) Mutations in the alternatively spliced exons of USH1C cause non-syndromic recessive deafness. Hum Genet 111: 26–30.

64. WhitlonDS, GabelC, ZhangX (1996) Cochlear inner hair cells exist transiently in the fetal Bronx Waltzer (bv/bv) mouse. J Comp Neurol 364: 515–522.

65. KansakuA, HirabayashiS, MoriH, FujiwaraN, KawataA, et al. (2006) Ligand-of-Numb protein X is an endocytic scaffold for junctional adhesion molecule 4. Oncogene 25: 5071–5084.

66. DavisRJ, HardingM, MoayediY, MardonG (2008) Mouse Dach1 and Dach2 are redundantly required for Mullerian duct development. Genesis 46: 205–213.

67. HenriqueD, AdamJ, MyatA, ChitnisA, LewisJ, et al. (1995) Expression of a Delta homologue in prospective neurons in the chick. Nature 375: 787–790.

68. SternCD (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.

69. KiernanAE (2006) The paintfill method as a tool for analyzing the three-dimensional structure of the inner ear. Brain Res 1091: 270–276.

70. BaschML, OhyamaT, SegilN, GrovesAK (2011) Canonical Notch signaling is not necessary for prosensory induction in the mouse cochlea: insights from a conditional mutant of RBPjkappa. J Neurosci 31: 8046–8058.

71. XiaA, GaoSS, YuanT, OsbornA, BressA, et al. (2010) Deficient forward transduction and enhanced reverse transduction in the alpha tectorin C1509G human hearing loss mutation. Dis Model Mech 3: 209–223.

Štítky
Genetika Reprodukčná medicína

Článok vyšiel v časopise

PLOS Genetics


2014 Číslo 1
Najčítanejšie tento týždeň
Najčítanejšie v tomto čísle
Kurzy

Zvýšte si kvalifikáciu online z pohodlia domova

Eozinofilní granulomatóza s polyangiitidou
nový kurz
Autori: doc. MUDr. Martina Doubková, Ph.D.

Všetky kurzy
Prihlásenie
Zabudnuté heslo

Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.

Prihlásenie

Nemáte účet?  Registrujte sa