# The coordination of cell size control and cell cycle regulation at developmental extremes

> **NIH NIH R35** · DARTMOUTH COLLEGE · 2024 · $410,000

## Abstract

PROJECT SUMMARY/ABSTRACT
A fundamental question in cell biology is how cells measure and maintain their characteristic sizes. We use two
systems in Drosophila development to study cell size control that provide a natural system for uncoupling
growth and division: embryogenesis and oogenesis. The early embryo is an extremely large cell that
undergoes rapid divisions without cell growth, while the oocyte uses polyploid nurse cells to grow to a massive
size without dividing. In the embryo, the final cell size is determined by the nucleus to cytoplasm ratio (N/C
ratio). The N/C ratio controls a major developmental transition known as the mid-blastula transition (MBT)
where the cell cycle stops and zygotic transcription initiates. Recently, we discovered a surprising mechanism
for N/C-ratio sensing in the pre-MBT embryo. Hyper-abundant maternally provided histone H3 acts as a
competitive inhibitor of the DNA-damage checkpoint kinase, Chk1, to prevent cell cycle slowing. As more and
more nuclei are generated by the successive divisions the pool of “free” (ie-not chromatin-incorporated) H3 is
imported into the increasing numbers of nuclei and then incorporated into chromatin thereby releasing Chk1
inhibition to allow cell cycle slowing once a threshold N/C ratio is reached. In oogenesis, polyploid nurse cells
generate the maternal supply of materials required for the egg and “dump” their contents into the oocyte to
achieve the correct volume. Histone biogenesis appears to play a role in regulating progression through
oogenesis as well, though the molecular mechanism is unclear. Over the next five years, work in this R35
MIRA proposal will: 1) interrogate the molecular mechanisms by which maternally provided H3 contributes to
cell size sensing at the MBT; 2) understand how the N/C ratio affects nuclear and chromatin composition
leading up to the MBT; and 3) extend the lab’s current models of cell size sensing to the growing egg chamber.
These projects will further the long-term goal of understanding cell size and cell cycle control in a diverse array
of tissue types and developmental timepoints. The resulting insights will expand our understanding of
fundamental processes shared by most living cells but that are obscured in other model systems by the tight
coupling between cell size and cell cycle progression.

## Key facts

- **NIH application ID:** 10933430
- **Project number:** 5R35GM150853-02
- **Recipient organization:** DARTMOUTH COLLEGE
- **Principal Investigator:** Amanda A Amodeo
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $410,000
- **Award type:** 5
- **Project period:** 2023-09-22 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933430

## Citation

> US National Institutes of Health, RePORTER application 10933430, The coordination of cell size control and cell cycle regulation at developmental extremes (5R35GM150853-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10933430. Licensed CC0.

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