# Ronin (Thap11) in Neural Crest Cell Development

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2020 · $520,018

## Abstract

PROJECT SUMMARY/ABSTRACT
 Neural crest cells (NCCs) are a transient, multipotent, migratory population of embryonic cells, which give
rise to a remarkable array of tissues including the craniofacial skeleton. Disruption of the cellular and molecular
mechanisms driving NCC specification, migration, and/or differentiation causes craniofacial disorders representing
approximately one-third of all babies born with birth defects. Thus, our long-term goal is to define the NCC gene
regulatory network that confers such specialized properties. In this proposal, we will determine whether the
transcription factor RONIN (THAP11) directs cranial NCC development by direct transcriptional regulation of
cobalamin (vitamin B12) coenzyme biosynthesis. We will also define the contribution of RONIN misregulation to the
pathophysiology of a newly discovered human syndrome called cblX. In preliminary studies, we found that Ronin is
expressed throughout the developing NCC population and that conditional knockout (CKO) of Ronin caused NCC-
derived craniofacial skeletal agenesis without grossly altering other NCC derivatives in the heart, peripheral nervous
system and enteric system. These data indicate that the osteochondrogenic NCC lineage is uniquely sensitive to
loss of Ronin. We also recently identified Mmachc as a direct transcriptional target of RONIN. MMACHC regulates
cobalamin coenzyme production and human mutations in MMACHC cause a combined methylmalonic acidemia
and homocystinuria designated cblC. CblC is the most common inborn error of intracellular cobalamin metabolism
and often presents as a multisystem disease predominantly impacting hematologic and neurologic development.
There are additional reports of craniofacial dysmorphias. Also, mutations in RONIN and its co-factor HCFC1 were
recently identified in a cblC-like syndrome, cblX. These data have led to us to hypothesize that the craniofacial
defects observed in Ronin mutants are a result of dysregulation of the cobalamin metabolic pathway in cranial
NCCs. To test this, we will perform a series of Ronin loss-of-function, genetic interaction, and rescue experiments.
We will also determine the functionality of the cobalamin metabolic pathway within wild type and mutant NCCs.
Upon successful completion of these aims, we expect to have identified a transcriptional mechanism that links
cobalamin metabolism to NCC differentiation into the craniofacial skeleton. This better understanding of NCC
development may ultimately inform more efficacious regenerative medicine strategies and lead to new therapeutic
targets for craniofacial defects.

## Key facts

- **NIH application ID:** 9978042
- **Project number:** 5R01DE028298-02
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Ross Anthony Poche
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $520,018
- **Award type:** 5
- **Project period:** 2019-07-15 → 2024-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9978042

## Citation

> US National Institutes of Health, RePORTER application 9978042, Ronin (Thap11) in Neural Crest Cell Development (5R01DE028298-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9978042. Licensed CC0.

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