Affecting Function Causes a Dilated Heart in Adult
Drosophila is a well recognized model of several human diseases, and recent investigations have demonstrated that Drosophila can be used as a model of human heart failure. Previously, we described that optical coherence tomography (OCT) can be used to rapidly examine the cardiac function in adult, awake flies. This technique provides images that are similar to echocardiography in humans, and therefore we postulated that this approach could be combined with the vast resources that are available in the fly community to identify new mutants that have abnormal heart function, a hallmark of certain cardiovascular diseases. Using OCT to examine the cardiac function in adult Drosophila from a set of molecularly-defined genomic deficiencies from the DrosDel and Exelixis collections, we identified an abnormally enlarged cardiac chamber in a series of deficiency mutants spanning the rhomboid 3 locus. Rhomboid 3 is a member of a highly conserved family of intramembrane serine proteases and processes Spitz, an epidermal growth factor (EGF)–like ligand. Using multiple approaches based on the examination of deficiency stocks, a series of mutants in the rhomboid-Spitz–EGF receptor pathway, and cardiac-specific transgenic rescue or dominant-negative repression of EGFR, we demonstrate that rhomboid 3 mediated activation of the EGF receptor pathway is necessary for proper adult cardiac function. The importance of EGF receptor signaling in the adult Drosophila heart underscores the concept that evolutionarily conserved signaling mechanisms are required to maintain normal myocardial function. Interestingly, prior work showing the inhibition of ErbB2, a member of the EGF receptor family, in transgenic knock-out mice or individuals that received herceptin chemotherapy is associated with the development of dilated cardiomyopathy. Our results, in conjunction with the demonstration that altered ErbB2 signaling underlies certain forms of mammalian cardiomyopathy, suggest that an evolutionarily conserved signaling mechanism may be necessary to maintain post-developmental cardiac function.
Vyšlo v časopise:
Affecting Function Causes a Dilated Heart in Adult. PLoS Genet 6(5): e32767. doi:10.1371/journal.pgen.1000969
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1000969
Souhrn
Drosophila is a well recognized model of several human diseases, and recent investigations have demonstrated that Drosophila can be used as a model of human heart failure. Previously, we described that optical coherence tomography (OCT) can be used to rapidly examine the cardiac function in adult, awake flies. This technique provides images that are similar to echocardiography in humans, and therefore we postulated that this approach could be combined with the vast resources that are available in the fly community to identify new mutants that have abnormal heart function, a hallmark of certain cardiovascular diseases. Using OCT to examine the cardiac function in adult Drosophila from a set of molecularly-defined genomic deficiencies from the DrosDel and Exelixis collections, we identified an abnormally enlarged cardiac chamber in a series of deficiency mutants spanning the rhomboid 3 locus. Rhomboid 3 is a member of a highly conserved family of intramembrane serine proteases and processes Spitz, an epidermal growth factor (EGF)–like ligand. Using multiple approaches based on the examination of deficiency stocks, a series of mutants in the rhomboid-Spitz–EGF receptor pathway, and cardiac-specific transgenic rescue or dominant-negative repression of EGFR, we demonstrate that rhomboid 3 mediated activation of the EGF receptor pathway is necessary for proper adult cardiac function. The importance of EGF receptor signaling in the adult Drosophila heart underscores the concept that evolutionarily conserved signaling mechanisms are required to maintain normal myocardial function. Interestingly, prior work showing the inhibition of ErbB2, a member of the EGF receptor family, in transgenic knock-out mice or individuals that received herceptin chemotherapy is associated with the development of dilated cardiomyopathy. Our results, in conjunction with the demonstration that altered ErbB2 signaling underlies certain forms of mammalian cardiomyopathy, suggest that an evolutionarily conserved signaling mechanism may be necessary to maintain post-developmental cardiac function.
Zdroje
1. BoniniNM
FortiniME
2003 Human neurodegenerative disease modeling using Drosophila. Annu Rev Neurosci 26 627 656
2. KimIM
WolfMJ
RockmanHA
Gene Deletion Screen for Cardiomyopathy in Adult Drosophila Identifies a New Notch Ligand. Circ Res
3. OcorrK
AkasakaT
BodmerR
2007 Age-related cardiac disease model of Drosophila. Mech Ageing Dev 128 112 116
4. VidalM
CaganRL
2006 Drosophila models for cancer research. Curr Opin Genet Dev 16 10 16
5. WolfMJ
AmreinH
IzattJA
ChomaMA
ReedyMC
2006 Drosophila as a model for the identification of genes causing adult human heart disease. Proc Natl Acad Sci U S A 103 1394 1399
6. ParksAL
CookKR
BelvinM
DompeNA
FawcettR
2004 Systematic generation of high-resolution deletion coverage of the Drosophila melanogaster genome. Nat Genet 36 288 292
7. ThibaultST
SingerMA
MiyazakiWY
MilashB
DompeNA
2004 A complementary transposon tool kit for Drosophila melanogaster using P and piggyBac. Nat Genet 36 283 287
8. FreemanM
2002 A fly's eye view of EGF receptor signalling. EMBO J 21 6635 6642
9. SchweitzerR
HowesR
SmithR
ShiloBZ
FreemanM
1995 Inhibition of Drosophila EGF receptor activation by the secreted protein Argos. Nature 376 699 702
10. SchweitzerR
ShaharabanyM
SegerR
ShiloBZ
1995 Secreted Spitz triggers the DER signaling pathway and is a limiting component in embryonic ventral ectoderm determination. Genes Dev 9 1518 1529
11. UrbanS
LeeJR
FreemanM
2001 Drosophila rhomboid-1 defines a family of putative intramembrane serine proteases. Cell 107 173 182
12. UrbanS
LeeJR
FreemanM
2002 A family of Rhomboid intramembrane proteases activates all Drosophila membrane-tethered EGF ligands. EMBO J 21 4277 4286
13. WassermanJD
UrbanS
FreemanM
2000 A family of rhomboid-like genes: Drosophila rhomboid-1 and roughoid/rhomboid-3 cooperate to activate EGF receptor signaling. Genes Dev 14 1651 1663
14. YogevS
SchejterED
ShiloBZ
2008 Drosophila EGFR signalling is modulated by differential compartmentalization of Rhomboid intramembrane proteases. EMBO J 27 1219 1230
15. BrownKE
FreemanM
2003 Egfr signalling defines a protective function for ommatidial orientation in the Drosophila eye. Development 130 5401 5412
16. BuffE
CarmenaA
GisselbrechtS
JimenezF
MichelsonAM
1998 Signalling by the Drosophila epidermal growth factor receptor is required for the specification and diversification of embryonic muscle progenitors. Development 125 2075 2086
17. GallioM
EnglundC
KylstenP
SamakovlisC
2004 Rhomboid 3 orchestrates Slit-independent repulsion of tracheal branches at the CNS midline. Development 131 3605 3614
18. BodmerR
VenkateshTV
1998 Heart development in Drosophila and vertebrates: conservation of molecular mechanisms. Dev Genet 22 181 186
19. BourBA
O'BrienMA
LockwoodWL
GoldsteinES
BodmerR
1995 Drosophila MEF2, a transcription factor that is essential for myogenesis. Genes Dev 9 730 741
20. MedioniC
AstierM
ZmojdzianM
JaglaK
SemerivaM
2008 Genetic control of cell morphogenesis during Drosophila melanogaster cardiac tube formation. J Cell Biol 182 249 261
21. Santiago-MartinezE
SoplopNH
PatelR
KramerSG
2008 Repulsion by Slit and Roundabout prevents Shotgun/E-cadherin-mediated cell adhesion during Drosophila heart tube lumen formation. J Cell Biol 182 241 248
22. YinZ
FraschM
1998 Regulation and function of tinman during dorsal mesoderm induction and heart specification in Drosophila. Dev Genet 22 187 200
23. CurtisNJ
RingoJM
DowseHB
1999 Morphology of the pupal heart, adult heart, and associated tissues in the fruit fly, Drosophila melanogaster. J Morphol 240 225 235
24. MonierB
AstierM
SemerivaM
PerrinL
2005 Steroid-dependent modification of Hox function drives myocyte reprogramming in the Drosophila heart. Development 132 5283 5293
25. ZeitouniB
SenatoreS
SeveracD
AkninC
SemerivaM
2007 Signalling pathways involved in adult heart formation revealed by gene expression profiling in Drosophila. PLoS Genet 3 e174 doi:10.1371/journal.pgen.0030174
26. LeeJH
BudanovAV
ParkEJ
BirseR
KimTE
Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327 1223 1228
27. CollinsKA
KorcarzCE
LangRM
2003 Use of echocardiography for the phenotypic assessment of genetically altered mice. Physiol Genomics 13 227 239
28. OcorrKA
CrawleyT
GibsonG
BodmerR
2007 Genetic variation for cardiac dysfunction in Drosophila. PLoS ONE 2 e601 doi:10.1371/journal.pone.0000601
29. PaternostroG
VignolaC
BartschDU
OmensJH
McCullochAD
2001 Age-associated cardiac dysfunction in Drosophila melanogaster. Circ Res 88 1053 1058
30. RockmanHA
OnoS
RossRS
JonesLR
KarimiM
1994 Molecular and physiological alterations in murine ventricular dysfunction. Proc Natl Acad Sci U S A 91 2694 2698
31. Taghli-LamallemO
AkasakaT
HoggG
NudelU
YaffeD
2008 Dystrophin deficiency in Drosophila reduces lifespan and causes a dilated cardiomyopathy phenotype. Aging Cell 7 237 249
32. TanakaN
DaltonN
MaoL
RockmanHA
PetersonKL
1996 Transthoracic echocardiography in models of cardiac disease in the mouse. Circulation 94 1109 1117
33. StrongLC
1920 Rhoughoid, a mutant located to the left of sepia in the third chromosome of Drosophila melanogaster. Biol Bull Wood's Hole 38 33 37
34. KumarJP
MosesK
2001 The EGF receptor and notch signaling pathways control the initiation of the morphogenetic furrow during Drosophila eye development. Development 128 2689 2697
35. LesokhinAM
YuSY
KatzJ
BakerNE
1999 Several levels of EGF receptor signaling during photoreceptor specification in wild-type, Ellipse, and null mutant Drosophila. Dev Biol 205 129 144
36. BergmannA
TugentmanM
ShiloBZ
StellerH
2002 Regulation of cell number by MAPK-dependent control of apoptosis: a mechanism for trophic survival signaling. Dev Cell 2 159 170
37. KumarJP
TioM
HsiungF
AkopyanS
GabayL
1998 Dissecting the roles of the Drosophila EGF receptor in eye development and MAP kinase activation. Development 125 3875 3885
38. TioM
MaC
MosesK
1994 spitz, a Drosophila homolog of transforming growth factor-alpha, is required in the founding photoreceptor cells of the compound eye facets. Mech Dev 48 13 23
39. McDonaldJA
PinheiroEM
KadlecL
SchupbachT
MontellDJ
2006 Multiple EGFR ligands participate in guiding migrating border cells. Dev Biol 296 94 103
40. ReichA
ShiloBZ
2002 Keren, a new ligand of the Drosophila epidermal growth factor receptor, undergoes two modes of cleavage. EMBO J 21 4287 4296
41. FreemanM
1996 Reiterative use of the EGF receptor triggers differentiation of all cell types in the Drosophila eye. Cell 87 651 660
42. McGuireSE
LePT
OsbornAJ
MatsumotoK
DavisRL
2003 Spatiotemporal rescue of memory dysfunction in Drosophila. Science 302 1765 1768
43. McGuireSE
RomanG
DavisRL
2004 Gene expression systems in Drosophila: a synthesis of time and space. Trends Genet 20 384 391
44. KimIM
WolfMJ
2009 Serial examination of an inducible and reversible dilated cardiomyopathy in individual adult Drosophila. PLoS ONE 4 e7132 doi:10.1371/journal.pone.0007132
45. YuX
SharmaKD
TakahashiT
IwamotoR
MekadaE
2002 Ligand-independent dimer formation of epidermal growth factor receptor (EGFR) is a step separable from ligand-induced EGFR signaling. Mol Biol Cell 13 2547 2557
46. BrownKE
KerrM
FreemanM
2007 The EGFR ligands Spitz and Keren act cooperatively in the Drosophila eye. Dev Biol 307 105 113
47. Neuman-SilberbergFS
SchupbachT
1993 The Drosophila dorsoventral patterning gene gurken produces a dorsally localized RNA and encodes a TGF alpha-like protein. Cell 75 165 174
48. Neuman-SilberbergFS
SchupbachT
1996 The Drosophila TGF-alpha-like protein Gurken: expression and cellular localization during Drosophila oogenesis. Mech Dev 59 105 113
49. AllikianMJ
BhabhaG
DospoyP
HeydemannA
RyderP
2007 Reduced life span with heart and muscle dysfunction in Drosophila sarcoglycan mutants. Hum Mol Genet 16 2933 2943
50. AlvaradoD
KleinDE
LemmonMA
2009 ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Nature 461 287 291
51. CroneSA
ZhaoYY
FanL
GuY
MinamisawaS
2002 ErbB2 is essential in the prevention of dilated cardiomyopathy. Nat Med 8 459 465
52. LemmensK
DoggenK
De KeulenaerGW
2007 Role of neuregulin-1/ErbB signaling in cardiovascular physiology and disease: implications for therapy of heart failure. Circulation 116 954 960
53. OzcelikC
ErdmannB
PilzB
WettschureckN
BritschS
2002 Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy. Proc Natl Acad Sci U S A 99 8880 8885
54. LembergMK
FreemanM
2007 Functional and evolutionary implications of enhanced genomic analysis of rhomboid intramembrane proteases. Genome Res 17 1634 1646
55. LohiO
UrbanS
FreemanM
2004 Diverse substrate recognition mechanisms for rhomboids; thrombomodulin is cleaved by Mammalian rhomboids. Curr Biol 14 236 241
56. PascallJC
BrownKD
2004 Intramembrane cleavage of ephrinB3 by the human rhomboid family protease, RHBDL2. Biochem Biophys Res Commun 317 244 252
57. BrandAH
PerrimonN
1993 Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 118 401 415
58. BaroloS
CarverLA
PosakonyJW
2000 GFP and beta-galactosidase transformation vectors for promoter/enhancer analysis in Drosophila. Biotechniques 29 726, 728, 730, 732
59. OcorrK
ReevesNL
WessellsRJ
FinkM
ChenHS
2007 KCNQ potassium channel mutations cause cardiac arrhythmias in Drosophila that mimic the effects of aging. Proc Natl Acad Sci U S A 104 3943 3948
60. AlayariNN
VoglerG
Taghli-LamallemO
OcorrK
BodmerR
2009 Fluorescent labeling of Drosophila heart structures. J Vis Exp 32
61. BainbridgeSP
BownesM
1981 Staging the metamorphosis of Drosophila melanogaster. J Embryol Exp Morphol 66 57 80
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2010 Číslo 5
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Common Genetic Variants near the Brittle Cornea Syndrome Locus Influence the Blinding Disease Risk Factor Central Corneal Thickness
- The Relationship among Gene Expression, the Evolution of Gene Dosage, and the Rate of Protein Evolution
- SMA-10/LRIG Is a Conserved Transmembrane Protein that Enhances Bone Morphogenetic Protein Signaling
- Manipulation of Behavioral Decline in with the Rag GTPase