# CRK regulation of ribosome biogenesis and craniofacial development

> **NIH NIH F31** · YALE UNIVERSITY · 2020 · $46,320

## Abstract

PROJECT SUMMARY/ABSTRACT
Background and Overall Hypothesis: Ribosome biogenesis, the process by which the protein synthesizing
machinery is produced, is essential and required in all cells. Mutations in factors required for ribosome production
give rise to a subset of diseases called ribosomopathies. These diseases are surprisingly characterized by
tissue-specific abnormalities despite the essential role of ribosomes in all cell types. Craniofacial specific defects,
occurring in established ribosomopathies such as Treacher Collins syndrome, manifest from neural crest cell
sensitivity to the nucleolar stress response during embryonic development. Miller-Dieker lissencephaly
syndrome caused by microdeletion (17p13.3) also leads to craniofacial abnormalities, but with no defined
molecular mechanism or connection to ribosome biogenesis thus far. These microdeletion phenotypes are
further defined by inclusion of CRK resulting in more severe craniofacial defects. Accordingly, CRK’s role in
development has been more precisely established with Crk (-/-) null mice exhibiting improper nasal development
and cleft palate. CRK is a protooncogenic adapter protein that is present in several signaling pathways controlling
cellular outputs such as proliferation and migration. Recently, the Baserga laboratory identified an additional role
for CRK as a novel human ribosome biogenesis factor through a genome-wide siRNA screen in MCF10A breast
epithelial cells (Farley-Barnes et al 2018). My preliminary results indicate that CRK depletion leads to inhibition
of early pre-rRNA processing steps in ribosome biogenesis through controlling the stability of the essential U8
small nucleolar RNA (snoRNA). Furthermore, I have identified a promising CRK-mediated pathway for controlling
U8 stability by U8 snoRNA trimethyl guanosine cap removal via the DCP2 decapping enzyme. I hypothesize
that this newly identified role of CRK in ribosome biogenesis contributes to its importance in craniofacial
development. Specific Aims: I propose to elucidate the molecular mechanisms underlying CRK’s control of
human ribosome biogenesis in tissue culture cells. I will test for changes in U8 snoRNA and DCP2 protein
localization and U8 snoRNA trimethyl guanosine cap abundance upon CRK depletion. Then I will test whether
CRK directly interacts with the DCP2 containing decapping complex. Secondly, I will determine the extent to
which CRK’s essential role in craniofacial development is connected to its role in ribosome biogenesis in the
model organism Xenopus tropicalis. I will use morpholino oligos and CRISPR to deplete and knockout crk so
that I can observe changes in embryonic morphology, neural crest development, pre-rRNA processing, and p53
nucleolar stress response induction. My proposed work will define CRK’s molecular role in craniofacial
development through its connection to ribosome biogenesis for the first time. Additionally, my work will provide
insight into the molecular basis of riboso...

## Key facts

- **NIH application ID:** 10141515
- **Project number:** 1F31DE030332-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Mason McCool
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $46,320
- **Award type:** 1
- **Project period:** 2020-09-29 → 2023-09-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10141515

## Citation

> US National Institutes of Health, RePORTER application 10141515, CRK regulation of ribosome biogenesis and craniofacial development (1F31DE030332-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10141515. Licensed CC0.

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