# Specialized Translational Control of Stem Cell Differentiation and Embryonic Development

> **NIH NIH R01** · STANFORD UNIVERSITY · 2022 · $602,131

## Abstract

Control of gene expression in space and time plays an important role in enabling cells to “know” where they are in the
developing embryo and what to become, a process often referred to as cellular specification. Decades of research have
demonstrated numerous layers of regulation in control of gene expression, at both the transcriptional and post-transcriptional
level, which coordinate this process. Translational control of gene expression has, on the contrary, received less
experimental attention. Most notably, the prevailing dogma has been that at the level of protein production, the ribosome -
although an immensely complex molecular machine- possesses a constitutive rather than regulatory function in translating
mRNAs. Our findings have established a new field of study by demonstrating that ribosomes are highly regulatory in control
of the expression of developmental gene regulatory networks underlying tissue patterning and formation of the mammalian
body plan. In our most recent studies, we have identified entire biological pathways in embryonic stem cells represented
by the translational preferences of specific ribosomes, that differ in the composition of their ribosomal proteins (RPs) or the
interaction of novel ribosome-associated proteins (RAPs) that we have recently identified that directly associate with
mammalian ribosomes. We have further shown ribosome heterogeneity in proximity to key cellular organelles as a
mechanism to control localized protein production within subcellular space. These findings change our understanding of
gene regulation and open a new portal of study into an additional layer of gene expression vital to control of cell
specification, tissue patterning, and embryonic development. In this proposal we will undertake a highly multidisciplinary
approach to characterize this novel regulatory code for translational control of the circuitry of key developmental networks.
In Aim1 we will extend our new roadmap of ribosome heterogeneity indicated by the presence of distinct ribosomes during
primary human ES cellular differentiation to an organismal level. In particular, we will leverage novel genetic tools to study
ribosome biology in-vivo. Using this approach, we will delineate the mechanisms by which a single RP can control a
paramount step in embryonic development, namely sustained paraxial mesoderm formation, and its role in translational
control of the WNT signaling pathway, which reflects a novel step in the regulation of a major signaling pathway in
development. In Aim2 we will undertake a systems level approach to characterize the role of ribosomes as key regulators
of cell fate transitions. We will utilize novel technologies to forcibly and inducibly remove specific RPs selectively from
cytoplasmic ribosomes for the first time and assess their individual functions on stem cells differentiation down the
mesoderm and endoderm lineages. In Aim3 we will functionally characterize alternative RP paralogs in mammary-glad...

## Key facts

- **NIH application ID:** 10377513
- **Project number:** 5R01HD086634-07
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Maria Barna
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $602,131
- **Award type:** 5
- **Project period:** 2016-03-15 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10377513

## Citation

> US National Institutes of Health, RePORTER application 10377513, Specialized Translational Control of Stem Cell Differentiation and Embryonic Development (5R01HD086634-07). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10377513. Licensed CC0.

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