# Selective mRNA translation in developmental disorders

> **NIH NIH R01** · FRED HUTCHINSON CANCER CENTER · 2022 · $528,000

## Abstract

Abstract
RASopathies cause the majority of congenital disorders affecting nearly 1 in 1000 individuals. In particular,
mutations in RAS-MAPK pathway genes lead to distinct pathologies including craniofacial dysmorphology,
mental impairment, musculoskeletal defects, and a predisposition to cancer. Although presentations may vary
between different mutations, nearly all RASopathies share common skin growth abnormalities. At a genetic
level, germline mutations to RAS pathway members including Hras and Kras are known to cause these defects
which are best exemplified by Costello, Noonan, and Cardiofaciocutaneous syndromes. For years,
comprehensive interrogation of RAS in development has been limited to genome-wide studies of DNA and
RNA. While important, these investigations have left translation-based mechanisms largely untouched. This is
remarkable in light of emerging evidence that developmental disorders, such as Diamond-Blackfan Anemia
and Schwachman-Diamond and Treacher Collins syndromes (reviewed in Tahmasebi et al., 2018), are
causally linked to impairments in the translation apparatus. Thus, our current knowledge of the mechanistic
basis of RASopathies is incomplete, which is a barrier to therapeutic innovation. Our long-term goal is to
uncover the mechanism of Ras-mediated tissue growth, which will ultimately yield innovative therapies to
restore normal tissue homeostasis without compromising housekeeping functions during development. Using
skin as a defined model of tissue development we have discovered that hyperactive Hras simultaneously
drives specialized proliferation and differentiation programs by rewiring the translation initiation machinery
through eIF2B5. Utilizing state-of-the-art in vivo genetic screens pioneered in our laboratory, we have
determined the regulon of genes that eIF2B5 governs to impact self-renewal and cell fate choice. Remarkably,
these mRNA networks are clearly demarcated by their function with ubiquitination emerging as a key regulator
of cellular differentiation. As such, we hypothesize that activation of Ras promotes translation of a subset of
mRNAs that support non-physiological tissue growth during development, where increased stem cell
proliferation is balanced by their loss through differentiation into post-mitotic progeny. In this proposal we will
use a confluence of in vivo models, intra-vital microscopy, and newly developed cellular and molecular assays
to delineate how the interplay between RAS and eIF2B5 influences tissue dynamics. We will accomplish the
following Aims: 1) Uncover how eIF2B5-dependent ubiquitin ligases directs progenitor renewal and fate choice;
and 2) Elucidate how activated Hras and eIF2B5 direct mRNA specific translation to regulate progenitor
renewal. Collectively, the successful completion of our Aims will provide a new understanding of cellular and
molecular principles that support Ras-driven non-physiological growth during development. Ultimately, these
new insights will inform ...

## Key facts

- **NIH application ID:** 10652419
- **Project number:** 5R01GM135362-04
- **Recipient organization:** FRED HUTCHINSON CANCER CENTER
- **Principal Investigator:** Slobodan Beronja
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $528,000
- **Award type:** 5
- **Project period:** 2020-06-18 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10652419

## Citation

> US National Institutes of Health, RePORTER application 10652419, Selective mRNA translation in developmental disorders (5R01GM135362-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10652419. Licensed CC0.

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