# Transcriptional Control of the Formation of a Ciliated Epithelium by Downstream Mediators and Regulators of the Hippo Signaling Pathway

> **NIH NIH R01** · UNIVERSITY OF VIRGINIA · 2021 · $331,075

## Abstract

Project summary
 Dysfunction in generating and maintaining properly differentiated ciliated epithelia with motile cilia results in
a number of human ciliopathies that can lead to hydrocephalus, congenital heart defects, respiratory infections,
situs inversus and/or infertility. Whereas components involved in the assembly, structure and movement of
motile of cilia have been identified, little is known about the transcriptional control of ciliogenesis. Here we
seek to fill this gap by investigating the transcriptional regulation of the formation of a ciliated epithelium using
the Kupffer's vesicle (KV) of the zebrafish embryo as a model system. This ciliated organ functions as the fish
left-right organizer and develops, soon after gastrulation, from its precursors, the Dorsal Forerunner Cells
(DFCs).
 We recently identified the transcription factors and cofactors known to mediate or to regulate the
transcriptional outcome of the Hippo signaling pathway to be master regulators of DFCs differentiation. We
discovered that they act upstream of major signaling pathways and key transcription factors known to control
the formation of the KV and that they regulate, in the DFCs, the expression of epigenetic modifying enzymes.
In particular, we found that Hippo transcription factors and cofactors control the activity of Nodal signaling
during differentiation of the DFCs into KV, a previously unknown role for this pathway.
 We propose three aims to elucidate the mechanisms by which Hippo transcription factors and cofactors
control the formation of the ciliated epithelium of the KV. First, we will characterize the transcriptional network
that is directly and indirectly regulated by each of these factors. We will then perform functional analyzes on
selected direct target genes to identify novel functions required for the formation of the ciliated epithelium of the
KV. Second, we will explore the functional relationships between Hippo transcription factors and cofactors via
rescue experiments and analysis of their physical interactions. We will challenge the current model of their
interaction during normal development, previously established in a cancer cell culture system, and in which
they are thought to act antagonistically. Third, we will investigate the mechanisms by which Hippo transcription
cofactors control Nodal activity, for example by a transcriptional control of writers of DNA methylation marks.
 The completion of these studies will greatly advance our knowledge of the mechanisms by which a ciliated
epithelium is programmed at the transcriptional level. In addition, by providing a new model of interaction
between Hippo downstream mediators and regulators during normal development, and defining tissue-specific
transcriptional control of epigenetics by Hippo transcription factors and cofactors, our results will greatly
expand our knowledge of Hippo signaling pathway. Finally, insights gained about the generation and
maintenance of a properly differenti...

## Key facts

- **NIH application ID:** 10115083
- **Project number:** 5R01GM132131-03
- **Recipient organization:** UNIVERSITY OF VIRGINIA
- **Principal Investigator:** Christine THISSE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $331,075
- **Award type:** 5
- **Project period:** 2019-04-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10115083

## Citation

> US National Institutes of Health, RePORTER application 10115083, Transcriptional Control of the Formation of a Ciliated Epithelium by Downstream Mediators and Regulators of the Hippo Signaling Pathway (5R01GM132131-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10115083. Licensed CC0.

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