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PMID:20181743

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Citation

Xia, S, Li, X, Johnson, T, Seidel, C, Wallace, DP and Li, R (2010) Polycystin-dependent fluid flow sensing targets histone deacetylase 5 to prevent the development of renal cysts. Development 137:1075-84

Abstract

Polycystin 1 and polycystin 2 are large transmembrane proteins, which, when mutated, cause autosomal dominant polycystic kidney disease (ADPKD), a highly prevalent human genetic disease. The polycystins are thought to form a receptor-calcium channel complex in the plasma membrane of renal epithelial cells and elicit a calcium influx in response to mechanical stimulation, such as fluid flow across the apical surface of renal epithelial cells. The functional role of the polycystins in mechanosensation remains largely unknown. Here, we found that myocyte enhancer factor 2C (MEF2C) and histone deacetylase 5 (HDAC5), two key regulators of cardiac hypertrophy, are targets of polycystin-dependent fluid stress sensing in renal epithelial cells in mice. We show that fluid flow stimulation of polarized epithelial monolayers induced phosphorylation and nuclear export of HDAC5, which are crucial events in the activation of MEF2C-based transcription. Kidney-specific knockout of Mef2c, or genetrap-inactivation of a MEF2C transcriptional target, MIM, resulted in extensive renal tubule dilation and cysts, whereas Hdac5 heterozygosity or treatment with TSA, an HDAC inhibitor, reduced cyst formation in Pkd2(-/-) mouse embryos. These findings suggest a common signaling motif between myocardial hypertrophy and maintenance of renal epithelial architecture, and a potential therapeutic approach to treat ADPKD.

Links

PubMed PMC2835323 Online version:10.1242/dev.049437

Keywords

Animals; Cells, Cultured; Epithelial Cells/cytology; Epithelial Cells/metabolism; Female; Gene Expression Profiling; Histone Deacetylase Inhibitors/metabolism; Histone Deacetylases/genetics; Histone Deacetylases/metabolism; Humans; Kidney Tubules/cytology; Kidney Tubules/metabolism; Kidney Tubules/pathology; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Microarray Analysis; Myogenic Regulatory Factors/genetics; Myogenic Regulatory Factors/metabolism; Polycystic Kidney Diseases/genetics; Polycystic Kidney Diseases/metabolism; Polycystic Kidney Diseases/pathology; Rheology; Shear Strength; TRPP Cation Channels/genetics; TRPP Cation Channels/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:MEF2C

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MEF2C

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MEF2C

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:MTSS1

involved_in

GO:2001013: epithelial cell proliferation involved in renal tubule morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MTSS1

involved_in

GO:0061333: renal tubule morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MTSS1

involved_in

GO:0050680: negative regulation of epithelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MTSS1

involved_in

GO:0072160: nephron tubule epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MTSS1

involved_in

GO:0072102: glomerulus morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MTSS1

involved_in

GO:0071498: cellular response to fluid shear stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HDAC5

involved_in

GO:0000122: negative regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HDAC5

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HDAC5

enables

GO:0000978: RNA polymerase II cis-regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:HDAC5

enables

GO:0001227: DNA-binding transcription repressor activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

  • occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:PKD1

involved_in

GO:0006611: protein export from nucleus

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PKD1

involved_in

GO:0018105: peptidyl-serine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PKD2

involved_in

GO:0061333: renal tubule morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:PKD2

involved_in

GO:0010628: positive regulation of gene expression

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HDAC5

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:HDAC5

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:HDAC5

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:HDAC5

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HDAC5

involved_in

GO:0061333: renal tubule morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:HDAC5

involved_in

GO:0071498: cellular response to fluid shear stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0035984: cellular response to trichostatin A

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:MEF2C

enables

GO:0001228: DNA-binding transcription activator activity, RNA polymerase II-specific

ECO:0000315: mutant phenotype evidence used in manual assertion

F

occurs_at:(SO:0001952)

Seeded From UniProt

complete

MOUSE:MEF2C

enables

GO:0000978: RNA polymerase II proximal promoter sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0045944: positive regulation of transcription by RNA polymerase II

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0050680: negative regulation of epithelial cell proliferation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0061333: renal tubule morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0071498: cellular response to fluid shear stress

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0072102: glomerulus morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:0072160: nephron tubule epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:MEF2C

involved_in

GO:2001013: epithelial cell proliferation involved in renal tubule morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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