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PMID:24934224

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Citation

Ma, L, Quigley, I, Omran, H and Kintner, C (2014) Multicilin drives centriole biogenesis via E2f proteins. Genes Dev. 28:1461-71

Abstract

Multiciliate cells employ hundreds of motile cilia to produce fluid flow, which they nucleate and extend by first assembling hundreds of centrioles. In most cells, entry into the cell cycle allows centrioles to undergo a single round of duplication, but in differentiating multiciliate cells, massive centriole assembly occurs in G0 by a process initiated by a small coiled-coil protein, Multicilin. Here we show that Multicilin acts by forming a ternary complex with E2f4 or E2f5 and Dp1 that binds and activates most of the genes required for centriole biogenesis, while other cell cycle genes remain off. This complex also promotes the deuterosome pathway of centriole biogenesis by activating the expression of deup1 but not its paralog, cep63. Finally, we show that this complex is disabled by mutations in human Multicilin that cause a severe congenital mucociliary clearance disorder due to reduced generation of multiple cilia. By coopting the E2f regulation of cell cycle genes, Multicilin drives massive centriole assembly in epithelial progenitors in a manner required for multiciliate cell differentiation.

Links

PubMed PMC4083089 Online version:10.1101/gad.243832.114

Keywords

Animals; Centrioles/metabolism; E2F Transcription Factors/genetics; E2F Transcription Factors/metabolism; Gene Expression Regulation, Developmental; Mice; Mutation/genetics; Protein Binding/genetics; Skin/cytology; Skin/metabolism; Transcription Factor DP1/metabolism; Xenopus Proteins/genetics; Xenopus Proteins/metabolism; Xenopus laevis/genetics; Xenopus laevis/metabolism

Significance

Annotations

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

XENLA:MCIN

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q6DE14

F

Seeded From UniProt

complete

XENLA:MCIN

enables

GO:0003713: transcription coactivator activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

XENLA:MCIN

involved_in

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

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:MCIN

involved_in

GO:0044458: motile cilium assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:MCIN

involved_in

GO:0098534: centriole assembly

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:MCIN

involved_in

GO:1903251: multi-ciliated epithelial cell differentiation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:E2F4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q08B36

F

Seeded From UniProt

complete

XENLA:E2F4

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

XENLA:E2F4

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

XENLA:E2F4

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:E2F4

involved_in

GO:0098534: centriole assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:E2F4

involved_in

GO:1903251: multi-ciliated epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:Q6DE14

involved_in

GO:0044458: motile cilium assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:Q6DE14

involved_in

GO:0098534: centriole assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

XENLA:Q6DE14

enables

GO:0003700: DNA-binding transcription factor activity

ECO:0000315: mutant phenotype evidence used in manual assertion

F

Seeded From UniProt

complete

XENLA:Q6DE14

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

XENLA:Q6DE14

involved_in

GO:1903251: multi-ciliated epithelial cell differentiation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

Notes

See also

References

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