The kidney regulates the volume and composition of body fluids. During embryonic development nephrons, the functional units of the kidney, form from intermediate mesoderm after it is induced to differentiate by ureteric bud contact (71). The goal of this project is to determine the role of Wnt genes in nephrogenesis and the mechanisms guiding ureteric bud formation and growth. Members of the Wnt gene family have been implicated in developmental regulation and Wnt-1 is expressed in embryonic spinal cord, a potent inducer of nephron formation in vitro (55,79). We demonstrate that fibroblasts expressing exogenous Wnt-1 trigger isolated intermediate mesoderm to differentiate into nephrons (32). Several members of the Wnt gene family are expressed in kidney and we will test whether any of these genes confer nephron-inducing activity to cultured fibroblasts (32,79,83). Wnt gene-products are secreted matrix-binding glycoproteins and it is likely that the nephron inducing protein(s) secreted by the ureteric bud are matrix associated (5,71). Fibroblast-free Wnt + extracellular matrices will be prepared and tested for nephron inducing activity in vitro. All models describing ureteric bud formation are based on the poorly characterized mechanisms mediating nephric duct growth (58). The temporal and spatial distribution of Wnt-11 mRNA raises the possibility that it plays a role in nephric duct morphogenesis. We will determine if persistent Wnt-11 expression perturbs this process. Using retroviral mediate gene transfer we will test whether the avian nephric duct and ureteric bud form exclusively by growth of the duct epithelium, or by growth of the duct and induced recruitment of cells from posterior intermediate mesoderm (48). This latter mechanism mediates nephric duct elongation during Xenopus development, and recent lineage analyses in our laboratory raise the possibility that the rat ureteric bud/renal collecting system grows in an similar manner (12). Lineage analyses testing the differentiated fate of isolated intermediate mesoderm will be strengthened using an additional histochemical marker to identify the ureteric bud/renal collecting system and an independent method of marking cells with a genomic tag. In addition, we will test whether RET, Sd, or Ld mutant intermediate mesoderm, like wild type, is competent to form the renal collecting system when co-cultured with homogeneously marked ureteric buds (40,45,74). Results of these experiments will test the hypothesis that renal collecting system morphogenesis in vivo is dependent on recruitment of cells from intermediate mesoderm.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK045218-05
Application #
2391450
Study Section
General Medicine B Study Section (GMB)
Project Start
1991-09-15
Project End
2000-03-31
Budget Start
1997-04-01
Budget End
1998-03-31
Support Year
5
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Physiology
Type
Schools of Medicine
DUNS #
201373169
City
New York
State
NY
Country
United States
Zip Code
10065
Lacko, Lauretta A; Hurtado, Romulo; Hinds, Samantha et al. (2017) Altered feto-placental vascularization, feto-placental malperfusion and fetal growth restriction in mice with Egfl7 loss of function. Development 144:2469-2479
Hurtado, Romulo; Smith, Carl S (2016) Hyperpolarization-activated cation and T-type calcium ion channel expression in porcine and human renal pacemaker tissues. J Anat 228:812-25
Hurtado, Romulo; Zewdu, Rediet; Mtui, James et al. (2015) Pbx1-dependent control of VMC differentiation kinetics underlies gross renal vascular patterning. Development 142:2653-64
Herzlinger, Doris; Hurtado, Romulo (2014) Patterning the renal vascular bed. Semin Cell Dev Biol 36:50-6
Hurtado, Romulo; Bub, Gil; Herzlinger, Doris (2014) A molecular signature of tissues with pacemaker activity in the heart and upper urinary tract involves coexpressed hyperpolarization-activated cation and T-type Ca2+ channels. FASEB J 28:730-9
Grinstein, Mor; Yelin, Ronit; Herzlinger, Doris et al. (2013) Generation of the podocyte and tubular components of an amniote kidney: timing of specification and a role for Wnt signaling. Development 140:4565-73
Herzlinger, Doris (2011) Upper urinary tract pacemaker cells join the GLI club. J Clin Invest 121:836-8
Hurtado, Romulo; Bub, Gil; Herzlinger, Doris (2010) The pelvis-kidney junction contains HCN3, a hyperpolarization-activated cation channel that triggers ureter peristalsis. Kidney Int 77:500-8
Wang, Gerald J; Brenner-Anantharam, Andrea; Vaughan, E Darracott et al. (2009) Antagonism of BMP4 signaling disrupts smooth muscle investment of the ureter and ureteropelvic junction. J Urol 181:401-7
Guillaume, Richard; Bressan, Michel; Herzlinger, Doris (2009) Paraxial mesoderm contributes stromal cells to the developing kidney. Dev Biol 329:169-75

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