# Mechanisms of trophoblast lineage formation: Impact on postimplantation placental development

> **NIH NIH R01** · MICHIGAN STATE UNIVERSITY · 2020 · $321,625

## Abstract

SUMMARY
Trophoblast lineage formation represents the first differentiation event in the life cycle of placental mammals.
This process begins in the preimplantation embryo and continues in the postimplantation conceptus. Failure to
accurately establish the trophoblast lineage has major consequences, including developmental arrest prior to
the blastocyst stage, implantation failure, early miscarriage, and placental abnormalities. The overall objective
of the proposed studies is to use mouse embryos, and mouse and human embryonic stem (ES) cells as model
systems to elucidate the transcriptional mechanisms that govern trophoblast lineage development. Preliminary
studies discovered a novel and critical role for transcription factor AP-2γ (TFAP2C) in triggering and regulating
key events that underlie trophoblast lineage development. The overall hypothesis is that TFAP2C is a key
orchestrator of trophoblast lineage formation in mice and humans, whose precise regulation during the window
of preimplantation development is critical for postimplantation placental development. Studies in Specific Aim 1
will determine the role of TFAP2C in mouse trophoblast lineage formation. Experiments will test the hypothesis
that TFAP2C induces a trophoblast cell-fate in preimplantation embryos by positively regulating the formation
of polar-outside cells. Work in Specific Aim 2 will define the molecular mechanism by which TFAP2C induces
a trophoblast gene expression program in mice. Experiments will test the hypothesis that TFAP2C establishes
a trophoblast gene expression program by forming a regulatory complex with transcription factor TEAD4 and
the HIPPO signaling protein YAP1. In Specific Aim 3 the importance of the TFAP2C-mediated mechanisms in
mouse preimplantation embryos on subsequent postimplantation placental development will be determined.
Experiments will test the hypothesis that precise regulation of Tfap2c during early development is essential for
proper continuation of trophoblast progenitor development in postimplantation embryos. Lastly, Specific Aim 4
will elucidate the role of TFAP2C in human trophoblast lineage development. Proposed experiments will test
the hypothesis that TFAP2C is required for trophoblast lineage formation and differentiation into functional
syncytiotrophoblasts and extravillous trophoblasts. Taken together, results of the proposed studies will provide
new insights into the regulatory role of TFAP2C in mouse and human trophoblast lineage development. The
knowledge gained from these studies will be highly relevant to understanding the molecular basis of early
embryonic loss and clinical reproductive disorders that are associated with abnormal placentation.

## Key facts

- **NIH application ID:** 9898405
- **Project number:** 5R01HD095371-03
- **Recipient organization:** MICHIGAN STATE UNIVERSITY
- **Principal Investigator:** Jason Glenn Knott
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $321,625
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9898405

## Citation

> US National Institutes of Health, RePORTER application 9898405, Mechanisms of trophoblast lineage formation: Impact on postimplantation placental development (5R01HD095371-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9898405. Licensed CC0.

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