# Decoding lineage and fate specification in the C. elegans embryo

> **NIH NIH R35** · UNIVERSITY OF PENNSYLVANIA · 2020 · $402,500

## Abstract

ABSTRACT
 Combinatorial regulation by developmentally regulated transcription factors play a central role in
defining which genes are regulated in each cell during development and disease, and allows the same factors
to play different roles in different cells. The C. elegans embryo is an ideal system for a comprehensive study of
the role of lineage history in the context-dependent regulation of cell fate because of its invariant lineage and
powerful experimental tools. We recently developed automated lineage tracing and expression mapping
methods for C. elegans embryogenesis and have built the “Expression Patterns in Caenorhabditis” (EPIC)
database that contains the expression of over 250 fluorescent reporters for transcription factor (TF) expression
in every cell of developing embryos. In our past work, we have shown the potential for this resource as a
starting point for defining mechanisms controlling development. While we will continue to map the expression
of novel regulators, the main focus of this proposal is to use this database and our methods to address poorly
understood questions in developmental biology. 1) How do cells know their lineage history and translate
this information into correct terminal cell fates? We have identified a set of ~15 lineage-specific TFs whose
expression distinguishes a group of progenitor cells for diverse tissues descended from the “ABpxp”
blastomeres. We plan to test whether these TFs are necessary and sufficient individually and in combination to
specify the lineage identity of these progenitor cells, and to identify their targets, by imaging and genomics
analysis of loss and gain-of-function mutants. We will complement this by a detailed analysis of the cis-
regulatory sequences controlling terminal differentiation genes to identify their upstream regulators. These
“top-down” and “bottom-up” approaches should eventually converge to a common regulatory network. 2) What
mechanisms allow reuse of the same regulator(s) for different purposes in different developmental
contexts, such as different lineages? We have identified two sets of genes, expressed in either posterior or
anterior daughter cells after cell division, both of which are regulated by the Wnt pathway. We will combine
enhancer fine-mapping, expression mapping of synthetic enhancers, and genome-wide binding assays for the
Wnt-regulated TF POP-1/TCF to determine how each gene's response (activation or repression) to this
pathway is regulated differently in different cells. 3) How does redundancy of genes and enhancers
influence developmental robustness? Redundancy is extremely common in the early embryo, and we will
test the hypothesis that this redundancy exists to ensure robust development in the face of environmental
variability by detailed phenotyping of mutants in different conditions. In summary, the work we propose will
begin to complete the early embryonic regulatory network and answer important questions about principles of
development th...

## Key facts

- **NIH application ID:** 9983726
- **Project number:** 5R35GM127093-03
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** John Isaac Murray
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9983726

## Citation

> US National Institutes of Health, RePORTER application 9983726, Decoding lineage and fate specification in the C. elegans embryo (5R35GM127093-03). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9983726. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*