Wildung, Merit

English

Multiple motile cilia are present on specialized epithelial cells lining the airways, reproductive ducts, and brain ventricles. Cilia beating contributes to fluid movement and particle transport along the multiciliated surfaces. Dysfunction of motile cilia leads to ciliopathies such as primary ciliary dyskinesia, which is mainly characterized by respiratory infections, infertility, and - in rare cases - hydrocephalus. Due to the diverse vital functions of motile cilia, multiciliogenesis must be tightly controlled at both the transcriptional and post-transcriptional level. We recently identified the tumor suppressor and transcription factor TAp73 as a central regulator of airway multiciliogenesis by activating the transcription of several different pro-ciliogenic factors. 
Here, we show that TAp73 elicits its pro-ciliogenic function not only in the airways but also in other multiciliated tissues, albeit to different extents. Depletion of TAp73 results in a profound loss of motile cilia accompanied by diminished expression of several pro-ciliogenic factors including Foxj1, Rfx2, Rfx3, and axonemal dyneins Dnai1 and Dnali1 in the murine male and female reproductive tracts. As male and female TAp73 KO mice are infertile, we propose that defective multiciliogenesis in these mice contributes to the infertility phenotype by preventing proper gamete and zygote transport. Interestingly, multiciliated cells of the brain ventricles of TAp73 KO mice maintain their multiciliogenesis program by upregulating two well-established drivers of multiciliogenesis, namely E2F4 and miR449. Consistently, mice depleted for both TAp73 and miR449 display defective brain multiciliogenesis as these mice possess less and shorter motile cilia in the choroid plexus, which might contribute to the observed hydrocephalus in these mice. In summary, our data show that the role of TAp73 in multiciliogenesis is tissue-dependent and the interplay between transcriptional and post-transcriptional regulators ensures the development of functional motile cilia.
As we have demonstrated that miR449 is involved in brain multiciliogenesis, we next aimed to evaluate the role of miR449 in another multiciliated tissue, namely the airways. Coordinated beating of airway cilia contributes to mucociliary clearance, thereby facilitating airway defense and ensuring proper respiratory function. Moreover, multiciliated cells also participate in bronchial epithelial regeneration, a process which is impaired in patients with chronic obstructive pulmonary disease (COPD) in addition to a defective mucociliary clearance. Here, for the first time, we report a link between cilia-related genes and miR449 in COPD patients using genome-wide transcriptome analysis. Since miR449 is strongly upregulated during mucociliary differentiation and bronchial epithelial regeneration, miR449 depletion in mice results in an impaired ciliated epithelial regeneration upon exposure to various damaging challenges. This shows that miR449 is an important contributor to mucociliary regeneration and it does so by targeting Aurora kinase A (AURKA), a key player in the ciliary disassembly pathway. Consequently, deficiency of miR449 in mice increases AURKA levels, reduces airway cilia upon challenge and mucociliary clearance, which thereby triggers spontaneous emphysematous manifestations of COPD. Thus, our study provides a connection between miR449, defective cilia maintenance, and COPD development.
Altogether, our study shows that miRNAs and tumor suppressors form a gene regulatory network to protect multiciliogenesis in different organs, thereby preventing the onset of diseases.2019-12-0

Georg-August-University Göttingen

MiRNAs and tumor suppressors form a gene regulatory network to protect multiciliogenesis

https://ediss.uni-goettingen.de/bitstream/11858/00-1735-0000-002E-E555-C/1/Dissertation__MeritWildung.pdf

MiRNAs and tumor suppressors form a gene regulatory network to protect multiciliogenesis

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Georg-August-University Göttingen