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  Transcription factor TAp73 and microRNA-449 complement each other to support multiciliogenesis.

Wildung, M., Esser, T. U., Grausam, K. B., Wiedwald, C., Volceanov-Hahn, L., Riedel, D., et al. (2019). Transcription factor TAp73 and microRNA-449 complement each other to support multiciliogenesis. Cell Death and Differentiation, (in press). doi:10.1038/s41418-019-0332-7.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0004-5B7D-B Version Permalink: http://hdl.handle.net/21.11116/0000-0004-5B81-4
Genre: Journal Article

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 Creators:
Wildung, M., Author
Esser, T. U., Author
Grausam, K. B., Author
Wiedwald, C., Author
Volceanov-Hahn, L., Author
Riedel, D.1, Author              
Beuermann, S., Author
Li, L., Author
Zylla, J., Author
Günther, A. K.2, Author              
Wienken, M., Author
Ercetin, E., Author
Han, Zh., Author
Bremmer, F., Author
Shomroni, O., Author
Andreas, S., Author
Zhao, H., Author
Lizé, M., Author
Affiliations:
1Facility for Electron Microscopy, MPI for biophysical chemistry, Max Planck Society, ou_578615              
2Department of Genes and Behavior, MPI for Biophysical Chemistry, Max Planck Society, ou_persistent34              

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 Abstract: Motile cilia serve vital functions in development, homeostasis, and regeneration. We recently demonstrated that TAp73 is an essential transcriptional regulator of respiratory multiciliogenesis. Here, we show that TAp73 is expressed in multiciliated cells (MCCs) of diverse tissues. Analysis of TAp73 mutant animals revealed that TAp73 regulates Foxj1, Rfx2, Rfx3, axonemal dyneins Dnali1 and Dnai1, plays a pivotal role in the generation of MCCs in male and female reproductive ducts, and contributes to fertility. However, the function of MCCs in the brain appears to be preserved despite the loss of TAp73, and robust activity of cilia-related networks is maintained in the absence of TAp73. Notably, TAp73 loss leads to distinct changes in ciliogenic microRNAs: miR34bc expression is reduced, whereas the miR449 cluster is induced in diverse multiciliated epithelia. Among different MCCs, choroid plexus (CP) epithelial cells in the brain display prominent miR449 expression, whereas brain ventricles exhibit significant increase in miR449 levels along with an increase in the activity of ciliogenic E2F4/MCIDAS circuit in TAp73 mutant animals. Conversely, E2F4 induces robust transcriptional response from miR449 genomic regions. To address whether increased miR449 levels in the brain maintain the multiciliogenesis program in the absence of TAp73, we deleted both TAp73 and miR449 in mice. Although loss of miR449 alone led to a mild ciliary defect in the CP, more pronounced ciliary defects and hydrocephalus were observed in the brain lacking both TAp73 and miR449. In contrast, miR449 loss in other MCCs failed to enhance ciliary defects associated with TAp73 loss. Together, our study shows that, in addition to the airways, TAp73 is essential for generation of MCCs in male and female reproductive ducts, whereas miR449 and TAp73 complement each other to support multiciliogenesis and CP development in the brain.

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Language(s): eng - English
 Dates: 2019-05-08
 Publication Status: Published online
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 Rev. Method: Peer
 Identifiers: DOI: 10.1038/s41418-019-0332-7
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Title: Cell Death and Differentiation
Source Genre: Journal
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