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First published online November 11, 2009
doi: 10.1242/10.1242/dev.037267

Development 136, 3979-3989 (2009)
Published by The Company of Biologists 2009
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Semaphorin3a regulates endothelial cell number and podocyte differentiation during glomerular development

Kimberly J. Reidy1, Guillermo Villegas1, Jason Teichman1, Delma Veron2, Wa Shen1, Juan Jimenez3, David Thomas4 and Alda Tufro2,*

1 Department of Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
2 Department of Pediatrics, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06520-8064, USA
3 Imaging Facility, Albert Einstein College of Medicine, Bronx, NY, USA
4 Department of Pathology, Albert Einstein College of Medicine, Bronx, NY, USA

* Author for correspondence (alda.tufro{at}yale.edu)

Accepted September 3, 2009

Semaphorin3a (Sema3a), a chemorepellant guidance protein, plays crucial roles in neural, cardiac and peripheral vascular patterning. Sema3a is expressed in the developing nephron, mature podocytes and collecting tubules. Sema3a acts as a negative regulator of ureteric bud branching, but its function in glomerular development has not been examined. Here we tested the hypothesis that Sema3a regulates glomerular vascular development using loss- and gain-of-function mouse models. Sema3a deletion resulted in defects in renal vascular patterning, excess endothelial cells within glomerular capillaries, effaced podocytes with extremely wide foot processes and albuminuria. Podocyte Sema3a overexpression during organogenesis resulted in glomerular hypoplasia, characterized by glomerular endothelial cell apoptosis, delayed and abnormal podocyte foot process development, a complete absence of slit diaphragms and congenital proteinuria. Nephrin, WT1 and VEGFR2 were downregulated in Sema3a-overexpressing kidneys. We conclude that Sema3a is an essential negative regulator of endothelial cell survival in developing glomeruli and plays a crucial role in podocyte differentiation in vivo. Hence, a tight regulation of Sema3a dosage is required for the establishment of a normal glomerular filtration barrier.

Key words: Semaphorin, Glomerular development, Podocyte differentiation, Endothelial cell migration, Mouse


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