Genomes and Genes
Kidney vascularization: semaphorin-mediated mechanisms.
Principal Investigator: Alda Tufro
Affiliation: Yale University
Abstract: The molecular basis of directional migration of endothelial cells and the patterning of the developing vasculature during kidney organogenesis are poorly understood. We showed that VEGF is a chemoattractant for endothelial cells and directs the migration of endothelial cells towards developing nephrons. Other guidance cues are necessarily involved to modulate vascular growth. The nature of these guidance cues is unknown. Two VEGF co-receptors, neuropilins 1 and 2 are also receptors for semaphorins 3A and 3F. Semaphorins are guidance proteins that induce axon chemorepulsion. Sema 3A decreases endothelial cell migration by competing with VEGF for neuropilin binding. We showed that sema 3A and 3F are expressed during renal morphogenesis and localize to renal epithelial cells in a complementary fashion to their receptors located in endothelial cells, suggesting that semaphorins are important for vascular patterning. The objectives of this proposal are to elucidate the mechanisms of endothelial cells directional migration leading to the spatial organization of the developing vasculature and the function of semaphorins 3A and 3F during kidney morphogenesis. We hypothesize that sema 3A and 3F produced by renal epithe!ial cells generate chemorepulsive cues that modulate VEGF's endothelial cell chemoattraction by creating boundaries to endothelial cell migration. The combinatorial possibilities of ligand binding for sema 3 A, sema 3F and VEGF to their shared receptors may result in "paths" for vessel formation. We also hypothesize that the scatter factor-like properties of semaphorins may be responsible, at least in part, for branching morphogenesis of renal epithelia. To test our hypotheses: 1) we will study the mechanims of sema 3A and sema 3F guidance cues for endothelial cell migration by live cell microscopy using co-culture, migration assays, and cell-specific overexpression of sema 3A and 3F in transgenic mice. 2) We will examine the function of semaphorins 3A and 3F in branching morphogenesis and tubulogenesis using tubular epithelial cells, organ cultures and transgenic mice. 3) We will examine the role of FAK and the downstream signaling mechanisms involved in semaphorin-mediated guidance and morphogenetic cues. This proposal should provide novel and important information regarding semaphorin-induced directional migration and advance our knowledge of the molecular mechanisms governing vascular spatial organization. Understanding the molecular basis of guidance cues for cell migration should enable us to generate new strategies for diagnosis and treatment of congenital renal abnormalities and to develop organogenesis in vitro.
Funding Period: 2003-03-10 - 2009-01-31
more information: NIH RePORT
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Department of Pediatrics and Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, New York, USA
Kidney Int 69:1564-9. 2006....
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Dept of Pediatrics Nephrology, Albert Einstein College of Medicine, 1300 Morris Park Ave, Forchheimer Bldg, Rm 708, Bronx, NY 10461, USA
Am J Physiol Renal Physiol 291:F422-8. 2006..VEGF-A functions in podocytes include promoting survival through VEGFR2, inducing podocin upregulation and increasing podocin/CD2AP interaction...
- Semaphorin 3C regulates endothelial cell function by increasing integrin activityNazifa Banu
Division of Nephrology, Department of Internal Medicine, Albert Einstein College of Medicine, Bronx, NY 10461 USA
FASEB J 20:2150-2. 2006....
- Crosstalk between VEGF-A/VEGFR2 and GDNF/RET signaling pathwaysAlda Tufro
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY 10461, USA
Biochem Biophys Res Commun 358:410-6. 2007..These findings provide evidence for a novel cooperative interaction between VEGFR2 and RET that mediates VEGF-A functions in ureteric bud cells...
- Semaphorin3a disrupts podocyte foot processes causing acute proteinuriaR Tapia
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York 10461, USA
Kidney Int 73:733-40. 2008..Our findings indicate that a balance of semaphorin3a to vascular endothelial growth factor-A may be important for glomerular filtration barrier homeostasis...
- Semaphorin3a inhibits ureteric bud branching morphogenesisAlda Tufro
Department of Pediatrics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Forchheimer Building, Room 708, Bronx, NY 10461, USA
Mech Dev 125:558-68. 2008..Collectively, these data suggest that Sema3a is an endogenous antagonist of ureteric bud branching and hence, plays a role in patterning the renal collecting system as a negative regulator...
- Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular developmentKimberly J Reidy
Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
Development 136:3979-89. 2009..Hence, a tight regulation of Sema3a dosage is required for the establishment of a normal glomerular filtration barrier...