Abstract
The biology of renal development has become increasingly complex because technical advances in genetics and cell biology have been used to study this aspect of embryogenesis. The molecular biology and genetics of renal development may seem inconsequential and frustrating to the practicing clinician, but insight into fundamental mechanisms of renal development are necessary to understand clinical breakthroughs that will occur in the future. As a basis for appreciating these concepts, specific paradigms of renal development are illustrated and the investigative strategies used to develop them are summarized in this article.
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References and Recommended Reading
Glassberg, KI: Normal and abnormal development of the kidney: a clinician’s interpretation of current knowledge. J Urol 2002, 167:2339–2351.
Horster MF, Braun GS, Huber SM: Embryonic renal epithelia: induction, nephrogenesis, and cell differentiation. Physiol Rev 1999, 79:1157–1191. This article presents an in-depth and comprehensive review of renal development.
Perantoni AO, Dove LF, Karavanova I: Basic fibroblast growth factor can mediate the early inductive events in renal development. Proc Natl Acad Sci U S A 1995, 92:4696–4700.
Liu ZZ, Kumar A, Ota K, et al.: Developmental regulation and the role of insulin and insulin receptor in metanephrogenesis. Proc Natl Acad Sci U S A 1997, 94:6758–6763.
Schuchardt A, D’agati V, Pachnis V, Constantini F: Renal agenesis and hypodysplasia in ret-k mutant mice result from defects in ureteric bud development. Development 1996, 122:1919–1929.
Lin LF, Doherty DH, Lile LD, et al.: GDNF: a glial cell linederived neurotrophic factor for midbrain dopaminergic neurons. Science 1993, 260:1130–1132.
Kotzbauer PT, Lampe PA, Heukeroth RO, et al.: Neurturin, a relative of glial-cell-line-derived neurotrophic factor. Nature 1996, 384:467–470.
Milbrant J, de Sauvage FJ, Fahrner TJ, et al.: Persephin, a novel neurotrophic factor related to GDNF and neurturin. Neuron 1998, 20:245–253.
Sanicola M, Hession C, Worley D, et al.: Glial cell line-derived neurotrophic factor-dependent RET activation can be mediated by two different cell-surface accessory proteins. Proc Natl Acad Sci U S A 1997, 94:6238–6243.
Jing S, Yu Y, Fang M, et al.: GFRalpha-2 and GFRalpha-3 are two new receptors for ligands of the GDNF family. J Biol Chem 1997, 272: 33111–33117.
Vega QC, Worby CA, Lechner MS, et al.: Glial cell line-derived neurotrophic factor activates the receptor tyrosine kinase RET and promotes kidney morphogenesis. Proc Natl Acad Sci U S A 1996, 93:10657–10661.
Hubbard SR, Mohammadi M, Schlessinger J: Autoregulatory mechanism in protein-tyrosine kinases. J Biol Chem 1998, 273:11987–11990.
Tsui-Pierchala BA, Ahrens RC, Crowder RJ, et al.: The long and short isoforms of Ret function as independent signaling complexes. J Biol Chem 2002, 277:34618–34625.
Mrowka C, Schedl A: Wilms’ tumor suppressor gene WT1: from structure to renal pathophysiologic features. J Am Soc Nephrol 2000, 11: S106-S115.
Varanasi R, Bardeesy N, Ghahremani M, et al.: Fine structure analysis of the WT1 gene in sporadic Wilms tumors. Proc Natl Acad Sci U S A 1994, 91:3554–3558.
Schumacher V, Schneider S, Figge A, et al.: Correlation of germline mutations and two-hit inactivation of the WT1 gene with Wilms’ tumors of stromal-predominant histology. Proc Natl Acad Sci U S A 1997, 94:3972–3977.
Patek CE, Little MH, Fleming S, et al.: A zinc finger truncation of murine WT1 results in the characteristic urogenital abnormalities of Denys-Drash syndrome. Proc Natl Acad Sci U S A 1999, 96:2931–2936.
Call KM, Glaser T, Ito C, et al.: Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms’ tumor locus. Cell 1990, 60:509–520.
Haber DA, Sohn RL, Buckler AJ, et al.: Alternative splicing and genomic structure of the Wilms’ tumor gene WT1. Proc Natl Acad Sci U S A 1991, 88:9618–9622.
Englert C, Vidal M, Maheswaran S, et al.: Truncated mutants alter the subnuclear localization of the wild-type protein. Proc Natl Acad Sci U S A 1995, 92:11960–11964.
English MA, Licht JD: Tumor-associated WT1 missense mutants indicate that transcriptional activation by WT1 is critical for growth control. J Biol Chem 1999, 19:13258–13263.
Stuart RO, Bush KT, Nigam SK: Changes in global gene expression patterns during development and maturation of the rat kidney. Proc Natl Acad Sci U S A 2001, 98:5649–5654.
Jones KL, Fletcher J, eds: Smith’s Recognizable Patterns of Human Malformation. Philadelphia: WB Saunders; 1997.
Sparagana SP, Roach SE: Tuberous sclerosis complex. Curr Opin Neurol 2000, 13:115–119.
Van Slegtenhorst M, de Hoogt R, Hermans C, et al.: Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997, 277:805–808.
The European Chromosome 16 Tuberous Sclerosis Consortium: Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993, 75:1305–1315.
Carsillo T, Astrinidis A, Henski EP: Mutations in the tuberous sclerosis complex gene TSC2 are a cause of sporadic pulmonary lymphangioleiomyomatosis. Proc Natl Acad Sci U S A 2000, 97:6085–6090.
Kobayashi T, Minowa O, Sugitani Y, et al.: A germ-line Tsc1 mutation causes tumor development and embryonic lethality that are similar, but not identical to, those caused by Tsc2 mutation in mice. Proc Natl Acad Sci U S A 2001, 98:8762–8767.
Rennebeck G, Kleymenova EV, Anderson R, et al.: Loss of function of the tuberous sclerosis 2 tumor suppressor gene results in embryonic lethality characterized by disrupted neuroepithelial growth and development. Proc Natl Acad Sci U S A 1998, 95:15629–15634.
Johnson M, Kerfoot C, Bushnell T, et al.: Hamartin and tuberin expression in human tissues. Mod Pathol 2001, 14:202–210.
Nellist M, van Slegtenhorst MA, Goebloed M, et al.: Characterization of the cytosolic tuberin-hamartin complex. J Biol Chem 1999, 274:35647–35652. This article demonstrates biochemical evidence for interaction between the gene products of TSC1 and TSC2.
Nellist M, Verhaaf B, Goedbloed MA, et al.: TSC2 missense mutations inhibit tuberin phosphorylation and prevent formation of the tuberin-hamartin complex. Hum Mol Genet 2001, 10:2889–2898.
Latif F, Tory K, Gnarra J, et al.: Identification of the von Hippel-Lindau disease tumor suppressor gene. Science 1993, 260:1317–1320.
Linehan WM, Zbar B, Klausner RD: Renal carcinoma. In The Genetic Basis of Human Cancer, edn 2. Edited by Vogelstein B, Kinzler K. New York: McGraw-Hill; 2002:449–474.
Gnarra JR, Tory K, Weng Y, et al.: Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 1994, 7:85–90.
Gnarra, JR, Ward JM, Porter FB, et al.: Defective placental vasculogenesis causes embryonic lethality in VHL-deficient mice. Proc Natl Acad Sci U S A 1997, 94:9102–9107.
Kamura T, Koepp DM, Conrad MN, et al.: Rbx1, a component of the VHL tumor suppressor complex and SCF ubiquitin ligase. Science 1999, 284:657–661. This paper reports the discovery of an additional component in the ubiquitin ligase complex involving VHL, and summarizes a similar mechanism found in other species.
Maxwell PH, Wiesener MS, Chang GW, et al.: The tumor suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature 1999, 399:271–275. This article demonstrates additional downstream events that are affected by VHL mutations.
Glassberg KI: Renal dysgenesis and cystic disease of the kidney. In Campbell’s Urology, edn 8. Edited by Kavoussi L, Walsh PC. Philadelphia: WB Saunders; 2002: 1925–1994.
Gabow PA: Autosomal dominant polycystic kidney disease. N Engl J Med 1993, 329:332–342.
Harris PC: Molecular basis of polycystic kidney disease: PKD1, PKD2, and PKHD1. Curr Opin Nephrol Hypertens 2002, 11:309–314.
Lu W, Peissel B, Babakhanlou H, et al.: Perinatal lethality with kidney and pancreas defects in mice with a targeted PKD1 mutation. Nat Genet 1997, 17:179–181.
Wu G, D’Agati V, Cai Y, et al.: Somatic inactivation of PKD2 results in polycystic kidney disease. Cell 1998, 93:177–188.
Ong ACM, Ward CJ, Butler RJ, et al.: Coordinate expression of the autosomal dominant polycystic kidney disease proteins, polycystin-2 and polycystin-1, in normal and cystic tissue. Am J Pathol 1999, 154:1721–1729.
Ward CJ, Turley H, Ong ACM, et al.: Polycystin, the polycystic kidney disease 1 protein, is expressed by epithelial cells in fetal, adult, and polycystic kidney. Proc Natl Acad Sci U S A 1996, 93:1524–1528.
Kim E, Arnould T, Sellin LK, et al.: The polycystic kidney disease 1 gene product modulates Wnt signaling. J Biol Chem 1999, 274:4947–4953.
Bhunia AK, Piontek K, Boletta A, et al.: PKD1 induces p21 and regulation of the cell cycle via direct activation of the JAKSTAT signaling pathway in a process requiring PKD2. Cell 2002, 109:157–168.
Cai Y, Maeda Y, Cedzich A, et al.: Identification and characterization of polycystin-2, the PKD2 gene product. J Biol Chem 1999, 274:28557–28565.
Gonzalez-Perret S, Kim K, Ibarra C, et al.: Polycystin-2, the protein mutated in autosomal dominant polycystic kidney disease (ADPKD), is a Ca2+-permeable nonselective cation channel. Proc Natl Acad Sci U S A 2001, 98:1182–1187.
Gallagher AR, Cedzich A, Gretz N, et al.: The polycystic kidney disease protein PKD2 interacts with Hax-1, a protein associated with the actin cytoskeleton. Proc Natl Acad Sci U S A 2000, 97:4017–4022.
Newby LJ, Street AJ, Zhao Y, et al.: Identification, characterization, and localization of a novel kidney polycystin-1-polycystin-2 complex. J Biol Chem 2002, 277:20763–20773. This paper presents biochemical evidence for the interaction between polycystin-1 and polycystin-2.
Tsiokas L, Kim E, Arnould T, et al.: Homo and heterodimeric interactions between the gene products of PKD1 and PKD2. Proc Natl Acad Sci U S A 1997, 94:6965–6970.
Onuchic LF, Furu L, Nagasawa Y, et al.: PKHD1, the polycystic kidney and hepatic disease 1 gene, encodes a novel large protein containing multiple immunoglobulin-like plexin-transcription-factor domains and parallel beta-helix 1 repeats. Am J Hum Genet 2002, 70:1305–1317.
Ward CJ, Hogan MC, Rossetti S, et al.: The gene mutated in autosomal recessive polycystic kidney disease encodes a large, receptor-like protein. Nat Genet 2002, 30:259–269.
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Kim, C.M., Glassberg, K.I. Molecular mechanisms of renal development. Curr Urol Rep 4, 164–170 (2003). https://doi.org/10.1007/s11934-003-0045-8
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DOI: https://doi.org/10.1007/s11934-003-0045-8