# Control of Cell Number in Developing Retina

> **NIH NIH R01** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $392,850

## Abstract

Project Summary / Abstract
My long-term scientific goal is to understand the molecular mechanisms that specify retina cell number. Using
the compound eye of Drosophila as an experimental model, my laboratory has discovered the Hippo pathway
as a central mechanism underlying this process. The core of the Hippo pathway comprises a kinase cascade
in which the Ste20 kinase Hippo (Hpo) phosphorylates and activates the NDR family kinase Warts (Wts).
Wts, in turn, phosphorylates and inactivates the oncoprotein Yorkie (Yki) by excluding it from the nucleus,
where it normally functions as a coactivator for the DNA-binding transcription factor Scalloped (Sd). Our
research further established a critical role for the Hippo pathway in controlling organ size in mammals,
underscoring the importance of Drosophila as a powerful model to discover universal developmental
mechanisms.
Despite recent progress, our understanding of the composition, mechanism and regulation of Hippo signaling
remains incomplete. Much of our recent efforts have focused on discovering the missing components of the
Hippo pathway, with the ultimate goal of defining a complete Hippo signaling network. In the current grant
period, we have filled several key gaps in our understanding of the Hippo pathway, including a functional link
between Hippo signaling and the innate immunity receptor Toll, spectrin as an upstream regulator of Hippo
signaling by modulating actomyosin, autoinhibition of Hpo activity mediated by the STRIPAK phosphatase
complex, a Hpo-like kinase that functions redundantly with Hpo, a histone methyltransferase complex recruited
by Yki to activate the transcription of Hippo target genes, and a zinc finger transcriptional repressor recruited by
Sd to repress the transcription of Hippo target genes. We further contributed to the Hippo research community
by developing a set of fly stocks that can be used to unequivocally validate any Hippo pathway regulators through
rigorous genetic epistasis test.
In the next grant period, we will further elucidate the molecular underpinnings of the Hippo pathway through the
following specific aims. First, we will dissect the molecular and cellular mechanisms by which spectrin and
actomyosin cytoskeletons regulate Hippo signaling in developing tissues. Second, we will identify upstream
tumor suppressors that regulate Hippo signaling by antagonizing the activity of the STRIPAK phosphatase
complex. These studies will allow us to define how the STRIPAK phosphatase complex functions as a central
hub that integrates diverse upstream inputs into the Hippo pathway. Lastly, we will characterize novel regulators
of Hippo signaling isolated from a sensitized screen for mutations that enhance a partial loss-of-Hippo phenotype
in the eye. This unbiased approach will shed light on previously unforeseen regulators/mechanisms underlying
the Hippo pathway. Besides revealing fundamental mechanisms of eye development, the proposed studies will
have general implic...

## Key facts

- **NIH application ID:** 10314026
- **Project number:** 5R01EY015708-18
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** DUOJIA PAN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $392,850
- **Award type:** 5
- **Project period:** 2004-08-01 → 2024-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10314026

## Citation

> US National Institutes of Health, RePORTER application 10314026, Control of Cell Number in Developing Retina (5R01EY015708-18). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10314026. Licensed CC0.

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