# Mapping cell fate flow and feedback control on vertebrate embryonic landscapes

> **NIH NIH DP2** · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · 2021 · $1,330,498

## Abstract

PROJECT SUMMARY
From the moment of conception until death, metazoans face relentless assault on their tissues, their cells, and their
genomes. The ability of intricately patterned biological tissues to dynamically withstand these challenges is essential
for adult life but is tested first – and perhaps most critically – during embryonic development. Early failures of
embryonic patterning can lead to rapid and premature lethality, long-lasting birth defects, and/or devastating
developmental disorders. Over the years, developmental biologists have made great progress in understanding
many of the links connecting environmental and genetic perturbations to their consequences in embryos, generally
by applying reductionist approaches (e.g. single-gene mutant phenotypes, single-clone fate mapping). However, a
significant proportion of human pregnancies still result in developmental defects or miscarriages of unknown cause.
At present, we also often fail to understand why certain perturbations result in failed embryogenesis in some
individuals, but not in others. One persisting challenge is that any model of developmental patterning must
simultaneously take into account many elements of a complex system: multiple cell types, each exerting both
intrinsic and non-autonomous behaviors, cell turnover dynamics, lineage relationships, and many hundreds of
genetic factors.
 To address these challenges, we are establishing a new experimental paradigm for studies of
developmental biology that leverages microfluidics, single-cell genomics, computational biology, and a powerful in
vivo molecular genetic model of vertebrate embryogenesis, the laboratory zebrafish (Danio rerio). Under this
paradigm, we seek a new form of biological reductionism: comprehensive, molecular decomposition of
vertebrate embryonic tissues into their constituent cell states, at an experimental scale not previously
accessible to developmental biologists (e.g. 104–106 single-cell measurements per experiment, combined with
whole-genome or whole-transcriptome resolution). In this application, we present our motivation and our vision for
the whole-embryo single-cell state landscape as a versatile experimental and conceptual platform for systems-
level interrogation of vertebrate embryogenesis. Using this landscape approach, we will systematically quantify
developmental robustness (i.e. “canalization”) of all embryonic tissues to identify reoccurring bottlenecks and
vulnerabilities that drive human birth defects. In parallel, we will dissect mechanisms for cell fate control that
direct the “flow” of cells down the embryonic landscape, particularly in contexts where individual cells differ in their
genetic and/or developmental fitness. Our experimental vision will therefore revisit fundamental questions in
developmental biology, formulated nearly 8 decades ago, but which have persisted until now as abstract principles
rather than as testable hypotheses. We anticipate this research program will accel...

## Key facts

- **NIH application ID:** 10245930
- **Project number:** 1DP2GM146258-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
- **Principal Investigator:** Daniel E Wagner
- **Activity code:** DP2 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $1,330,498
- **Award type:** 1
- **Project period:** 2021-09-23 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10245930

## Citation

> US National Institutes of Health, RePORTER application 10245930, Mapping cell fate flow and feedback control on vertebrate embryonic landscapes (1DP2GM146258-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10245930. Licensed CC0.

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