TRRAP is a central regulator of human multiciliated cell formation

Wang, Zhao; Plasschaert, Lindsey W.; Aryal, Shivani; Renaud, Nicole; Yang, Zinger; Choo-Wing, Rayman; Pessotti, Angelica D.; Kirkpatrick, Nathaniel D.; Cochran, Nadire; Carbone, Walter; Maher, Rob; Lindeman, Alicia; Russ, Carsten; Reece‐Hoyes, John S.; McAllister, Gregory; Hoffman, Gregory R.; Roma, Guglielmo; Jaffe, Ari

doi:10.1083/jcb.201706106

Cited by 15 publications

(23 citation statements)

References 56 publications

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“…TRRAP, a component of multiple histone acetyltransferase complexes was recently shown to be required for the initiation of the MCC gene expression program ‘downstream’ of the Notch signaling event (downstream in the same sense as described for Cdk2 above) ( Wang et al, 2018 ). TRRAP nuclear expression arises in prospective MCCs prior to Foxj1 expression.…”

Section: Resultsmentioning

confidence: 99%

Cyclin-dependent kinase control of motile ciliogenesis

Vladar

Stratton

Saal

et al. 2018

eLife

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Cycling cells maintain centriole number at precisely two per cell in part by limiting their duplication to S phase under the control of the cell cycle machinery. In contrast, postmitotic multiciliated cells (MCCs) uncouple centriole assembly from cell cycle progression and produce hundreds of centrioles in the absence of DNA replication to serve as basal bodies for motile cilia. Although some cell cycle regulators have previously been implicated in motile ciliogenesis, how the cell cycle machinery is employed to amplify centrioles is unclear. We use transgenic mice and primary airway epithelial cell culture to show that Cdk2, the kinase responsible for the G1 to S phase transition, is also required in MCCs to initiate motile ciliogenesis. While Cdk2 is coupled with cyclins E and A2 during cell division, cyclin A1 is required during ciliogenesis, contributing to an alternative regulatory landscape that facilitates centriole amplification without DNA replication.

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Section: Resultsmentioning

confidence: 99%

Cyclin-dependent kinase control of motile ciliogenesis

Vladar

Stratton

Saal

et al. 2018

eLife

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“…Similarly, genes that are mutated in human neonatal respiratory distress syndrome, such as those encoding surfactant proteins B and C, ABCA3 and the transcription factor FOXM1, have been shown to play key roles in alveolar development in mice ( Whitsett, 2014 ). The genetic manipulation of human adult airway epithelial cell cultures has also been used to identify transcription factors that are required for ciliated cell differentiation, and these are largely assumed to also function in the development of human embryonic airway ciliated cells ( Boon et al, 2014 ; Wang et al, 2018 ). However, until recently, experimental systems that allow a mechanistic investigation of the molecular regulation of human embryonic lung development have been available to only very few laboratories and progress has consequently been limited.…”

Section: An Introduction To Human Lung Developmentmentioning

confidence: 99%

Human lung development: recent progress and new challenges

2018

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Recent studies have revealed biologically significant differences between human and mouse lung development, and have reported new in vitro systems that allow experimental manipulation of human lung models. At the same time, emerging clinical data suggest that the origins of some adult lung diseases are found in embryonic development and childhood. The convergence of these research themes has fuelled a resurgence of interest in human lung developmental biology. In this Review, we discuss our current understanding of human lung development, which has been profoundly influenced by studies in mice and, more recently, by experiments using in vitro human lung developmental models and RNA sequencing of human foetal lung tissue. Together, these approaches are helping to shed light on the mechanisms underlying human lung development and disease, and may help pave the way for new therapies.

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“…The CDK1 and CEP164 interaction in the network could be explained by the fact that the ATM/ATR protein kinase phosphorylates CEP164 causing the activation of CHK1, which inhibits the cyclin-A-dependent activation of CDK1 and thus pauses the progression of the cell cycle [ 80 ]. We also observed the transactivation/transformation-domain-associated protein (TRRAP; regulator acting upstream of multicilin), which binds to upstream promoter region of several genes (associated with human ciliopathies) and regulate multi-ciliated cell differentiation and function [ 81 ]. Herceg and co-workers (2001) demonstrated that TRRAP is necessary for mitotic checkpoint and normal cell cycle progression.…”

Section: Structure and Composition Of The MCC Apparatus In Humansmentioning

confidence: 99%

Mucociliary Respiratory Epithelium Integrity in Molecular Defense and Susceptibility to Pulmonary Viral Infections

Adivitiya

Kaushik

Chakraborty

et al. 2021

Biology

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Mucociliary defense, mediated by the ciliated and goblet cells, is fundamental to respiratory fitness. The concerted action of ciliary movement on the respiratory epithelial surface and the pathogen entrapment function of mucus help to maintain healthy airways. Consequently, genetic or acquired defects in lung defense elicit respiratory diseases and secondary microbial infections that inflict damage on pulmonary function and may even be fatal. Individuals living with chronic and acute respiratory diseases are more susceptible to develop severe coronavirus disease-19 (COVID-19) illness and hence should be proficiently managed. In light of the prevailing pandemic, we review the current understanding of the respiratory system and its molecular components with a major focus on the pathophysiology arising due to collapsed respiratory epithelium integrity such as abnormal ciliary movement, cilia loss and dysfunction, ciliated cell destruction, and changes in mucus rheology. The review includes protein interaction networks of coronavirus infection-manifested implications on the molecular machinery that regulates mucociliary clearance. We also provide an insight into the alteration of the transcriptional networks of genes in the nasopharynx associated with the mucociliary clearance apparatus in humans upon infection by severe acute respiratory syndrome coronavirus-2.

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TRRAP is a central regulator of human multiciliated cell formation

Cited by 15 publications

References 56 publications

Cyclin-dependent kinase control of motile ciliogenesis

Cyclin-dependent kinase control of motile ciliogenesis

Human lung development: recent progress and new challenges

Mucociliary Respiratory Epithelium Integrity in Molecular Defense and Susceptibility to Pulmonary Viral Infections

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