GDNF signaling through the Ret receptor tyrosine kinase (RTK) is required for ureteric bud (UB) branching morphogenesis during kidney development in mice and humans. Furthermore, many other mutant genes that cause renal agenesis exert their effects via the GDNF/RET pathway. Therefore, RET signaling is believed to play a central role in renal organogenesis. Here, we re-examine the extent to which the functions of Gdnf and Ret are unique, by seeking conditions in which a kidney can develop in their absence. We find that in the absence of the negative regulator Spry1, Gdnf, and Ret are no longer required for extensive kidney development. Gdnf−/−;Spry1−/− or Ret−/−;Spry1−/− double mutants develop large kidneys with normal ureters, highly branched collecting ducts, extensive nephrogenesis, and normal histoarchitecture. However, despite extensive branching, the UB displays alterations in branch spacing, angle, and frequency. UB branching in the absence of Gdnf and Spry1 requires Fgf10 (which normally plays a minor role), as removal of even one copy of Fgf10 in Gdnf−/−;Spry1−/− mutants causes a complete failure of ureter and kidney development. In contrast to Gdnf or Ret mutations, renal agenesis caused by concomitant lack of the transcription factors ETV4 and ETV5 is not rescued by removing Spry1, consistent with their role downstream of both RET and FGFRs. This shows that, for many aspects of renal development, the balance between positive signaling by RTKs and negative regulation of this signaling by SPRY1 is more critical than the specific role of GDNF. Other signals, including FGF10, can perform many of the functions of GDNF, when SPRY1 is absent. But GDNF/RET signaling has an apparently unique function in determining normal branching pattern. In contrast to GDNF or FGF10, Etv4 and Etv5 represent a critical node in the RTK signaling network that cannot by bypassed by reducing the negative regulation of upstream signals.
Vyšlo v časopise: Kidney Development in the Absence of and Requires. PLoS Genet 6(1): e32767. doi:10.1371/journal.pgen.1000809 Kategorie: Research Article prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1000809
1. MooreMW
KleinRD
FarinasI
SauerH
ArmaniniM
1996 Renal and neuronal abnormalities in mice lacking GDNF. Nature 382 76 79
2. PichelJG
ShenL
ShengHZ
GranholmAC
DragoJ
1996 Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382 73 76
3. SanchezMP
Silos-SantiagoI
FrisenJ
HeB
LiraSA
1996 Renal agenesis and the absence of enteric neurons in mice lacking GDNF. Nature 382 70 73
4. SchuchardtA
D'AgatiV
Larsson-BlombergL
CostantiniF
PachnisV
1994 Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367 380 383
5. CostantiniF
ShakyaR
2006 GDNF/Ret signaling and the development of the kidney. Bioessays 28 117 127
6. SkinnerMA
SaffordSD
ReevesJG
JacksonME
FreemermanAJ
2008 Renal aplasia in humans is associated with RET mutations. Am J Hum Genet 82 344 351
7. SchedlA
2007 Renal abnormalities and their developmental origin. Nat Rev Genet 8 791 802
8. LuB
2009 Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nat Genet 41 1295 302
9. ChiX
MichosO
RiccioP
EnomotoH
2009 Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell 17 199 209
10. SainioK
SuvantoP
DaviesJ
WartiovaaraJ
WartiovaaraK
1997 Glial-cell-line-derived neurotrophic factor is required for bud initiation from ureteric epithelium. Development 124 4077 4087
11. SariolaH
SainioK
1997 The tip-top branching ureter. Curr Opin Cell Biol 9 877 884
12. PepicelliCV
KispertA
RowitchDH
McMahonAP
1997 GDNF induces branching and increased cell proliferation in the ureter of the mouse. Dev Biol 192 193 198
13. MichaelL
DaviesJA
2004 Pattern and regulation of cell proliferation during murine ureteric bud development. J Anat 204 241 255
14. TangMJ
WorleyD
SanicolaM
DresslerGR
1998 The RET-glial cell-derived neurotrophic factor (GDNF) pathway stimulates migration and chemoattraction of epithelial cells. J Cell Biol 142 1337 1345
15. TangMJ
CaiY
TsaiSJ
WangYK
2002 Ureteric bud outgrowth in response to RET activation is mediated by phosphatidylinositol 3-kinase. Dev Biol 243 128 136
16. SariolaH
SaarmaM
2003 Novel functions and signalling pathways for GDNF. J Cell Sci 116 3855 3862
17. BassonMA
AkbulutS
Watson-JohnsonJ
SimonR
CarrollTJ
2005 Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction. Dev Cell 8 229 239
18. BassonMA
HyinkD
2006 Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1. Dev Biol 299 466 477
19. MasonJM
MorrisonDJ
BassonMA
LichtJD
2006 Sprouty proteins: multifaceted negative-feedback regulators of receptor tyrosine kinase signaling. Trends Cell Biol 16 45 54
20. AyadaT
TaniguchiK
OkamotoF
KatoR
KomuneS
2009 Sprouty4 negatively regulates protein kinase C activation by inhibiting phosphatidylinositol 4,5-biphosphate hydrolysis. Oncogene 28 1076 1088
21. MaeshimaA
SakuraiH
ChoiY
KitamuraS
VaughnDA
2007 Glial cell-derived neurotrophic factor independent ureteric bud outgrowth from the Wolffian duct. J Am Soc Nephrol 18 3147 3155
22. SchuchardtA
1996 Renal agenesis and hypodysplasia in ret-k - mutant mice result from defects in ureteric bud development. Development 122 1919 1929
23. MackieGG
StephensFD
1975 Duplex kidneys: a correlation of renal dysplasia with position of the ureteral orifice. J Urol 114 274 280
24. IchikawaI
KuwayamaF
PopeJCt
MiyazakiY
2002 Paradigm shift from classic anatomic theories to contemporary cell biological views of CAKUT. Kidney Int 61 889 898
25. DaviesJA
MillarCB
JohnsonEMJr.
MilbrandtJ
1999 Neurturin: an autocrine regulator of renal collecting duct development. Dev Genet 24 284 292
26. AiraksinenMS
TitievskyA
1999 GDNF family neurotrophic factor signaling: four masters, one servant? Mol Cell Neurosci 13 313 325
27. ChiX
HadjantonakisAK
WuZ
2009 A transgenic mouse that reveals cell shape and arrangement during ureteric bud branching. Genesis 47 61 66
28. Schmidt-OttKM
YangJ
ChenX
WangH
ParagasN
2005 Novel regulators of kidney development from the tips of the ureteric bud. J Am Soc Nephrol 16 1993 2002
29. CaruanaG
Cullen-McEwenL
NelsonAL
KostouliasX
WoodsK
2006 Spatial gene expression in the T-stage mouse metanephros. Gene Expr Patterns 6 807 825
30. de GraaffE
SrinivasS
KilkennyC
MankooBS
2001 Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. Genes Dev 15 2433 2444
31. YuJ
RajagopalJ
KobayashiA
RenQ
2009 A Wnt7b-dependent pathway regulates the orientation of epithelial cell division and establishes the cortico-medullary axis of the mammalian kidney. Development 136 161 171
32. QiaoJ
BushKT
SteerDL
StuartRO
2001 Multiple fibroblast growth factors support growth of the ureteric bud but have different effects on branching morphogenesis. Mech Dev 109 123 135
33. OhuchiH
HoriY
YamasakiM
HaradaH
SekineK
2000 FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem Biophys Res Commun 277 643 649
34. QiaoJ
UzzoR
Obara-IshiharaT
DegensteinL
FuchsE
1999 FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development 126 547 554
35. MinH
DanilenkoDM
ScullySA
BolonB
RingBD
1998 Fgf-10 is required for both limb and lung development and exhibits striking functional similarity to Drosophila branchless. Genes Dev 12 3156 3161
36. ZhaoH
KeggH
GradyS
TruongHT
RobinsonML
2004 Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev Biol 276 403 415
37. BatourinaE
ChoiC
BelloN
HensleT
2002 Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Nat Genet 32 109 115
38. GrieshammerU
LeM
PlumpAS
WangF
Tessier-LavigneM
2004 SLIT2-mediated ROBO2 signaling restricts kidney induction to a single site. Dev Cell 6 709 717
39. KumeT
DengK
HoganBL
2000 Murine forkhead/winged helix genes Foxc1 (Mf1) and Foxc2 (Mfh1) are required for the early organogenesis of the kidney and urinary tract. Development 127 1387 1395
40. ShakyaR
JhoEH
KotkaP
KholodilovN
2005 The role of GDNF in patterning the excretory system. Dev Biol 283 70 84
41. MichosO
PanmanL
VinterstenK
BeierK
ZellerR
2004 Gremlin-mediated BMP antagonism induces the epithelial-mesenchymal feedback signaling controlling metanephric kidney and limb organogenesis. Development 131 3401 3410
42. MichosO
GoncalvesA
Lopez-RiosJ
TieckeE
NaillatF
2007 Reduction of BMP4 activity by gremlin 1 enables ureteric bud outgrowth and GDNF/WNT11 feedback signalling during kidney branching morphogenesis. Development 134 2397 2405
43. IshibeS
KarihalooA
MaH
ZhangJ
MarlierA
2009 Met and the epidermal growth factor receptor act cooperatively to regulate final nephron number and maintain collecting duct morphology. Development 136 337 345
44. RozenEJ
SchmidtH
DolcetX
JainS
2009 Loss of Sprouty1 rescues renal agenesis caused by Ret mutation. J Am Soc Nephrol 20 255 259
45. JainS
EncinasM
2006 Critical and distinct roles for key RET tyrosine docking sites in renal development. Genes Dev 20 321 333
46. TakahashiM
2001 The GDNF/RET signaling pathway and human diseases. Cytokine Growth Factor Rev 12 361 373
47. BellusciS
GrindleyJ
EmotoH
ItohN
1997 Fibroblast growth factor 10 (FGF10) and branching morphogenesis in the embryonic mouse lung. Development 124 4867 4878
48. WeaverM
DunnNR
2000 Bmp4 and Fgf10 play opposing roles during lung bud morphogenesis. Development 127 2695 2704
49. LivetJ
SigristM
StroebelS
De PaolaV
PriceSR
2002 ETS gene Pea3 controls the central position and terminal arborization of specific motor neuron pools. Neuron 35 877 892
50. ChenC
OuyangW
GriguraV
ZhouQ
CarnesK
2005 ERM is required for transcriptional control of the spermatogonial stem cell niche. Nature 436 1030 1034
51. ZunigaA
SpitzF
HaramisAP
2004 Mouse limb deformity mutations disrupt a global control region within the large regulatory landscape required for Gremlin expression. Genes Dev 18 1553 1564
Zvýšte si kvalifikáciu online z pohodlia domova
Nemáte účet? Registrujte sa
Zadajte e-mailovú adresu, s ktorou ste vytvárali účet. Budú Vám na ňu zasielané informácie k nastaveniu nového hesla.
