title: To bud or not to bud: the RET perspective in CAKUT.
abstract: Congenital anomalies of the kidneys or lower urinary tract (CAKUT) encompass a spectrum of anomalies that result from aberrations in spatio-temporal regulation of genetic, epigenetic, environmental, and molecular signals at key stages of urinary tract development. The Rearranged in Transfection (RET) tyrosine kinase signaling system is a major pathway required for normal development of the kidneys, ureters, peripheral and enteric nervous systems. In the kidneys, RET is activated by interaction with the ligand glial cell line-derived neurotrophic factor (GDNF) and coreceptor GFRα1. This activated complex regulates a number of downstream signaling cascades (PLCγ, MAPK, and PI3K) that control proliferation, migration, renewal, and apoptosis. Disruption of these events is thought to underlie diseases arising from aberrant RET signaling. RET mutations are found in 5-30 % of CAKUT patients and a number of Ret mouse mutants show a spectrum of kidney and lower urinary tract defects reminiscent of CAKUT in humans. The remarkable similarities between mouse and human kidney development and in defects due to RET mutations has led to using RET signaling as a paradigm for determining the fundamental principles in patterning of the upper and lower urinary tract and for understanding CAKUT pathogenesis. In this review, we provide an overview of studies in vivo that delineate expression and the functional importance of RET signaling complex during different stages of development of the upper and lower urinary tracts. We discuss how RET signaling balances activating and inhibitory signals emanating from its docking tyrosines and its interaction with upstream and downstream regulators to precisely modulate different aspects of Wolffian duct patterning and branching morphogenesis. We outline the diversity of cellular mechanisms regulated by RET, disruption of which causes malformations ranging from renal agenesis to multicystic dysplastic kidneys in the upper tract and vesicoureteral reflux or ureteropelvic junction obstruction in the lower tract.
authors.forename: T Keefe
authors.initials: TK
authors.lastname: Davis
authors.forename: Masato
authors.initials: M
authors.lastname: Hoshi
authors.forename: Sanjay
authors.initials: S
authors.lastname: Jain
mesh_terms: D000818:Animals; D006801:Humans; D038081:Organogenesis / Q000502:physiology; D051096:Proto-Oncogene Proteins c-ret / Q000502:physiology*; D014551:Urinary Tract / Q000002:abnormalities*; D014564:Urogenital Abnormalities / Q000235:genetics / Q000378:metabolism*; D014570:Urologic Diseases / Q000151:congenital*
chemical_list: D051096:Proto-Oncogene Proteins c-ret
references.citation: Mech Dev. 2013 Sep-Oct;130(9-10):506-18
references.pmid: 23542432
references.citation: Nat Genet. 2002 Sep;32(1):109-15
references.pmid: 12195422
references.citation: Dev Cell. 2004 May;6(5):709-17
references.pmid: 15130495
references.citation: Neuron. 2004 Nov 18;44(4):623-36
references.pmid: 15541311
references.citation: Mech Dev. 2007 Apr;124(4):290-303
references.pmid: 17300925
references.citation: Development. 2001 Dec;128(23):4747-56
references.pmid: 11731455
references.citation: Hum Genet. 2012 Nov;131(11):1725-38
references.pmid: 22729463
references.citation: Organogenesis. 2009 Oct;5(4):177-90
references.pmid: 20539737
references.citation: Nat Cell Biol. 2002 Nov;4(11):850-8
references.pmid: 12402043
references.citation: J Med Genet. 2011 Jul;48(7):497-504
references.pmid: 21490379
references.citation: J Am Soc Nephrol. 2012 Apr;23(4):750-63
references.pmid: 22302197
references.citation: PLoS Genet. 2010 Jan 15;6(1):e1000809
references.pmid: 20084103
references.citation: Cold Spring Harb Perspect Biol. 2013 Feb 01;5(2):
references.pmid: 23378586
references.citation: J Pediatr Urol. 2006 Feb;2(1):2-9
references.pmid: 18947587
references.citation: J Neurosci. 2006 Oct 25;26(43):11230-8
references.pmid: 17065462
references.citation: Am J Hum Genet. 2008 Feb;82(2):344-51
references.pmid: 18252215
references.citation: Exp Neurol. 1999 Aug;158(2):504-28
references.pmid: 10415156
references.citation: Neuron. 1999 Aug;23(4):725-36
references.pmid: 10482239
references.citation: Neuron. 1998 Jul;21(1):53-62
references.pmid: 9697851
references.citation: Proc Natl Acad Sci U S A. 1999 Jun 22;96(13):7330-5
references.pmid: 10377414
references.citation: Hum Mutat. 2009 Apr;30(4):548-56
references.pmid: 19177457
references.citation: Am J Physiol Renal Physiol. 2004 Dec;287(6):F1123-30
references.pmid: 15328070
references.citation: J Signal Transduct. 2011;2011:869281
references.pmid: 21637383
references.citation: Pediatr Nephrol. 2011 Sep;26(9):1419-25
references.pmid: 21365192
references.citation: Dev Cell. 2005 Jan;8(1):65-74
references.pmid: 15621530
references.citation: Development. 2001 Dec;128(24):5173-80
references.pmid: 11748152
references.citation: Development. 2004 Nov;131(21):5503-13
references.pmid: 15469971
references.citation: Organogenesis. 2009 Jan;5(1):306-14
references.pmid: 19568352
references.citation: Development. 2010 Jan;137(2):283-92
references.pmid: 20040494
references.citation: J Am Soc Nephrol. 2008 Jan;19(1):151-7
references.pmid: 18057216
references.citation: J Clin Invest. 2009 Apr;119(4):924-35
references.pmid: 19273906
references.citation: Dev Cell. 2009 Aug;17(2):199-209
references.pmid: 19686681
references.citation: Nat Genet. 2009 Dec;41(12):1295-302
references.pmid: 19898483
references.citation: Mol Cell Biol. 2005 Nov;25(21):9661-73
references.pmid: 16227613
references.citation: Cell. 1985 Sep;42(2):581-8
references.pmid: 2992805
references.citation: Am J Physiol Renal Physiol. 2009 Nov;297(5):F1208-19
references.pmid: 19741018
references.citation: Dev Dyn. 2000 Feb;217(2):146-58
references.pmid: 10706139
references.citation: Dev Biol. 1997 Dec 1;192(1):193-8
references.pmid: 9405108
references.citation: J Neurosci. 2008 Feb 27;28(9):2131-46
references.pmid: 18305247
references.citation: J Clin Invest. 2010 Mar;120(3):778-90
references.pmid: 20160347
references.citation: Nat Rev Neurosci. 2002 May;3(5):383-94
references.pmid: 11988777
references.citation: Mol Cell Neurosci. 1999 May;13(5):313-25
references.pmid: 10356294
references.citation: Genes Dev. 2006 Feb 1;20(3):321-33
references.pmid: 16452504
references.citation: Dev Cell. 2010 May 18;18(5):698-712
references.pmid: 20493806
references.citation: J Am Soc Nephrol. 2013 Jan;24(1):19-25
references.pmid: 23123402
references.citation: Acta Crystallogr Sect F Struct Biol Cryst Commun. 2009 Jun 1;65(Pt 6):551-8
references.pmid: 19478429
references.citation: J Am Soc Nephrol. 2008 Oct;19(10):2027-34
references.pmid: 18820179
references.citation: Neuron. 1998 Aug;21(2):317-24
references.pmid: 9728913
references.citation: Nature. 1996 Jul 4;382(6586):73-6
references.pmid: 8657307
references.citation: Development. 2009 Dec;136(23):3863-74
references.pmid: 19906853
references.citation: Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):10657-61
references.pmid: 8855235
references.citation: Development. 1999 Apr;126(7):1375-86
references.pmid: 10068631
references.citation: J Am Soc Nephrol. 2009 Feb;20(2):255-9
references.pmid: 19056869
references.citation: Dev Biol. 2011 Dec 15;360(2):310-7
references.pmid: 22015719
references.citation: Development. 2006 Nov;133(22):4507-16
references.pmid: 17050626
references.citation: J Am Soc Nephrol. 2007 Dec;18(12):3147-55
references.pmid: 18003772
references.citation: Development. 2007 Jun;134(11):2171-81
references.pmid: 17507417
references.citation: Development. 2012 Jul;139(13):2405-15
references.pmid: 22627285
references.citation: J Cell Sci. 2003 Oct 1;116(Pt 19):3855-62
references.pmid: 12953054
references.citation: Nat Med. 2012 Feb 12;18(3):375-7
references.pmid: 22327624
references.citation: Exp Nephrol. 1998 Jul-Aug;6(4):337-51
references.pmid: 9690097
references.citation: Mol Cell Biol. 2004 Sep;24(18):8026-36
references.pmid: 15340065
references.citation: Dev Cell. 2005 Feb;8(2):229-39
references.pmid: 15691764
references.citation: Genes Dev. 2001 Sep 15;15(18):2433-44
references.pmid: 11562352
references.citation: Neuron. 1999 Feb;22(2):243-52
references.pmid: 10069331
references.citation: J Med Genet. 2008 Jan;45(1):1-14
references.pmid: 17965226
references.citation: Development. 2011 May;138(10):2089-97
references.pmid: 21521737
references.citation: Nature. 1994 Jan 27;367(6461):380-3
references.pmid: 8114940