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Control of multiciliogenesis by miR-34/449 in the male reproductive tract through enforcing cell cycle exit.

ABSTRACT: Multiciliated cells (MCCs) are terminally differentiated postmitotic cells that possess hundreds of motile cilia on their apical surface. Defects in cilia formation are associated with ciliopathies that affect many organs. In this study, we tested the role and mechanism of the miR-34/449 family in the regulation of multiciliogenesis in EDs using an miR-34b/c-/-; miR-449-/- double knockout (dKO) mouse model. MiR-34b/c and miR-449 depletion led to a reduced number of MCCs and abnormal cilia structure in the EDs starting from postnatal day (P)14. However, abnormal MCC differentiation in the dKO EDs could be observed as early as P7. RNA-seq analyses revealed that the aberrant development of MCCs in the EDs of dKO mice was associated with the upregulation of genes involved in cell cycle control. Using a cyclin-dependent kinase inhibitor to force cell cycle exit promoted MCC differentiation, and partially rescued the defective multiciliogenesis in the EDs of dKO mice. Taken together, our results suggest that miR-34b/c and miR-449 play an essential role in multiciliogenesis in EDs by regulating cell cycle exit.

SUBMITTER: Wu YJ

PROVIDER: S-EPMC8182409 | biostudies-literature |

REPOSITORIES: biostudies-literature

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miR-34/449 control apical actin network formation during multiciliogenesis through small GTPase pathways.

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Motile cilia of the male reproductive system require miR-34/miR-449 for development and function to generate luminal turbulence.

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

Project description: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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Characterizing isomiR variants within the microRNA-34/449 family.

Project description:miR-34/449 microRNAs are conserved regulators of multiciliated cell differentiation. Here, we evidence and characterize expression of two isomiR variant sequences from the miR-34/449 family in human airway epithelial cells. These isomiRs differ from their canonical counterparts miR-34b and miR-449c by one supplemental uridine at their 5'-end, leading to a one-base shift in their seed region. Overexpression of canonical miR-34/449 or 5'-isomiR-34/449 induces distinct gene expression profiles and biological effects. However, some target transcripts and functional activities are shared by both canonical microRNAs and isomiRs. Indeed, both repress important targets that result in cell cycle blockage and Notch pathway inhibition. Our findings suggest that 5'-isomiR-34/449 may represent additional mechanisms by which miR-34/449 family finely controls several pathways to drive multiciliogenesis.

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Gene expression changes in the respiratory epithelium of miR-34/449 knockout mice

Project description:MicroRNA ablation prevents multiciliogenesis via cell cycle deregulation MicroRNAs (miRNAs) have been implicated in various biological processes but have been most frequently described to inhibit proliferation and tumorigenesis. Here we describe an essential function of the miR-34/449 family during differentiation of multiciliated cells that is mediated by their well-described suppression of cell cycle progression. Constitutive deletion of all six members of this miRNA family triggers a derepression of multiple cell cycle-promoting proteins, thereby preventing epithelial cells from exiting the cell cycle and to maintain in a quiescent state. As a result, formation of motile multicilia is strongly inhibited in several tissues including the respiratory epithelium and the fallopian tube. Consequently, mice lacking miR-34/449 genes display infertility as well as severe chronic airway disease leading to postnatal death. These results show how miRNA-mediated repression of the cell cycle is required to allow multiciliogenesis to proceed during epithelial differentiation.

2017-09-12 | GSE92296 | GEO

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Project description:This SuperSeries is composed of the SubSeries listed below.

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