# Control of cell proliferation and differentiation by growth pathways

> **NIH NIH R35** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $665,330

## Abstract

PROJECT SUMMARY/ABSTRACT
The overall goal of our research program is to delineate molecular mechanisms that regulate cell
proliferation and differentiation in the context of animal development. This knowledge will help to advance
the understanding of normal processes in the developing multicellular organisms, explain why dysregulation
of these mechanisms leads to disease, and provide strategies to ameliorate these unwanted effects. We
focus on the highly conserved Retinoblastoma (RB) pathway, which is involved in plethora of biological
processes but is best known for its role in cell cycle control. One of the key targets of the RB pathway is the
E2F family of transcription factors that is negatively regulated by the Retinoblastoma protein (pRB).
Mammalian RB research has traditionally centered around its prominent role in cancer and therefore, its
function in development remains poorly understood. A major hurdle to studying the RB pathway in
mammalian development is redundancy and compensation, as the large multigene Rb and E2F families
make genetic analysis daunting. The Drosophila model system provides an attractive alternative because
the Drosophila RB pathway is highly conserved yet it is simpler. In previous years, we have focused on
identifying tissues and functions of E2F and Rbf, the fly pRB ortholog, that are essential for animal viability.
During these studies, we have found that the RB pathway is particularly important in adult skeletal muscle.
Surprisingly, in the muscle, both E2F and Rbf are needed in late muscle development to directly activate
the expression of metabolic genes. We will use genomics approaches coupled with genetic analysis to
investigate the molecular details of E2F/Rbf dependent activation. We will focus on the role of E2F/Rbf at
enhancers and how the loss of E2F/Rbf binding at these regulatory regions changes chromatin state and
gene expression. Previosuly, we have found that the phenotype of E2F deficient animals is a combination
of both tissue intrinsic and systemic effects. Our future research will build on this discovery to determine
why E2F inactivation in skeletal muscle leads to lethality. Another area of interest is focused on interaction
between the RB pathway and Hippo signaling pathway. Combined inactivation of both pathways leads to
photoreceptor dedifferentiation because the cells inappropriately turn on the eye progenitor transcriptional
program, which is dependent on Homothorax (Hth) and Yorkie, a transcriptional effector of the Hippo
pathway. Our future experiments will leverage the power of single cell genomics and single cell epigenomics
to determine the upstream regulatory events and identify the role of Hth-Yorkie in transcriptional regulation
in dedifferentiating photoreceptors and in normal eye progenitor cells. Collectively, the proposed research
will advance our understanding of normal development and animal physiology, and how perturbations in
growth pathways may lead to disease.

## Key facts

- **NIH application ID:** 10836833
- **Project number:** 2R35GM131707-06
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Maxim Frolov
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $665,330
- **Award type:** 2
- **Project period:** 2019-05-01 → 2029-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10836833

## Citation

> US National Institutes of Health, RePORTER application 10836833, Control of cell proliferation and differentiation by growth pathways (2R35GM131707-06). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10836833. Licensed CC0.

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