Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease

Fangming Lin, Thomas Hiesberger, Kimberly Cordes, Angus M. Sinclair, Lawrence S B Goldstein, Stefan Somlo, Peter Igarashi

Research output: Contribution to journalArticle

405 Citations (Scopus)

Abstract

Polycystic kidney disease (PKD) is the most common genetic cause of renal failure in humans. Several proteins that are encoded by genes associated with PKD have recently been identified in primary cilia in renal tubular epithelia. These findings have suggested that abnormalities in cilia formation and function may play a role in the pathogenesis of PKD. To directly determine whether cilia are essential to maintain tubular integrity, we conditionally inactivated KIF3A, a subunit of kinesin-II that is essential for cilia formation, in renal epithelia. Constitutive inactivation of KIF3A produces abnormalities of left-right axis determination and embryonic lethality. Here we show that tissue-specific inactivation of KIF3A in renal tubular epithelial cells results in viable offspring with normal-appearing kidneys at birth. Cysts begin to develop in the kidney at postnatal day 5 and cause renal failure by postnatal day 21. The cyst epithelial cells lack primary cilia and exhibit increased proliferation and apoptosis, apical mislocalization of the epidermal growth factor receptor, increased expression of β-catenin and c-Myc, and inhibition of p21cIP1. These results demonstrate that the absence of renal cilia produces both the clinical and cell biological findings associated with PKD. Most generally, the phenotype of Kif3a mutant mice suggests a role for primary cilia in the maintenance of lumen-forming epithelial differentiation.

Original languageEnglish (US)
Pages (from-to)5286-5291
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume100
Issue number9
DOIs
StatePublished - Apr 29 2003

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Polycystic Kidney Diseases
Cilia
Kidney
Renal Insufficiency
Cysts
Epithelium
Epithelial Cells
Catenins
kinesin-II
Epidermal Growth Factor Receptor
Maintenance
Parturition
Apoptosis
Phenotype

ASJC Scopus subject areas

  • Genetics
  • General

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Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. / Lin, Fangming; Hiesberger, Thomas; Cordes, Kimberly; Sinclair, Angus M.; Goldstein, Lawrence S B; Somlo, Stefan; Igarashi, Peter.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 100, No. 9, 29.04.2003, p. 5286-5291.

Research output: Contribution to journalArticle

Lin, Fangming ; Hiesberger, Thomas ; Cordes, Kimberly ; Sinclair, Angus M. ; Goldstein, Lawrence S B ; Somlo, Stefan ; Igarashi, Peter. / Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. In: Proceedings of the National Academy of Sciences of the United States of America. 2003 ; Vol. 100, No. 9. pp. 5286-5291.
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