# Temporal program for cell fate specification in the mouse embryo

> **NIH NIH R01** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $504,044

## Abstract

SUMMARY. The first cell fate decision in mammals transforms a totipotent embryo comprising identical cells into
two cell types: outer trophectoderm cells, which will give rise to the placenta, and inner pluripotent cells, which
will give rise to the fetus. This decision depends on cell polarization. Although we understand how cell
polarization connects to downstream signaling to specify the two cell types, the mechanisms that act earlier, to
ensure cell polarization and its specific developmental timing, remain entirely unknown. To identify this
mechanism, we first need to identify the upstream regulators, which have been elusive – until now. We recently
found that two zygotically expressed transcription factors, Tfap2c and Tead4, together with Rho-mediated
actomyosin activity, are essential and sufficient to trigger de novo cell polarization. These results provide us with
an unprecedented opportunity to determine the mechanism that triggers the specific developmental timing of
embryo polarization in early mammalian development. The objective of this proposal is to reveal the principles
of self-organization that lead to de novo polarization and consequently the first cell fate specification in the key
model mammalian embryo, the mouse embryo. Our central hypothesis is that zygotic transcription cooperates
with the cytoskeleton to polarize cells and drive the first cell fate determination. We will test this hypothesis via
the following Specific Aims: Aim 1: To determine what regulates timing of embryo polarization. We
hypothesize that the timing of embryo polarization is controlled by Tfap2c and Tead4. We will alter the dose and
developmental stage of Tfap2c and Tead4 expression and examine the effects on their downstream targets and
the timing of embryo polarization. Aim 2: To determine how the apical domain becomes established. We
hypothesize that Tfap2c and Tead4 regulate apical domain formation by modulating the actomyosin
cytoskeleton, which in turn controls the conjugation of Par complex clusters. We will use advanced imaging
techniques and pharmacological and optogenetic methods to determine the role of the actomyosin cytoskeleton
in regulating apical domain formation and the dynamics of the Par complex during polarization. We will also
examine how Tfap2c and Tead4 control the behavior of the actomyosin cytoskeleton and the organization of
apical proteins into clusters to form the apical domain. Aim 3: To determine how altered timing of polarization
affects embryo development. Embryo polarization always happens at the late 8-cell stage, just before the first
cell fate decision, suggesting that the invariant timing of this polarization is critical for subsequent developmental
progression. We will determine if accelerating the timing of embryo polarization by one cell cycle at the pre-
implantation stage affects subsequent development, specifically cell fate and blastocyst formation before
implantation and embryo morphogenesis post-implantati...

## Key facts

- **NIH application ID:** 10046014
- **Project number:** 1R01HD100456-01A1
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Magdalena Zernicka-Goetz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $504,044
- **Award type:** 1
- **Project period:** 2020-08-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046014

## Citation

> US National Institutes of Health, RePORTER application 10046014, Temporal program for cell fate specification in the mouse embryo (1R01HD100456-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10046014. Licensed CC0.

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