Ribosome biogenesis regulation of neural crest cell differentiation in development and disease

The National Institute of Dental and Craniofacial Research awarded the Stowers Institute for Medical Research $124,200 on September 1, 2026, under the Oral Diseases and Disorders Research program (CFDA 93.121) to investigate ribosome biogenesis regulation of neural crest cell differentiation in development and disease.

The funded research examines how ribosomal RNA transcription and ribosome biogenesis control neural crest cell fate acquisition and differentiation during craniofacial development. The project tests the hypothesis that increased RNA polymerase I-mediated ribosomal RNA transcription is essential for normal craniofacial morphogenesis by globally deleting POLR1A (the catalytic core of RNA polymerase I) in a temporal fashion in mice and examining effects on cartilage, bone, and sensory neuron progenitors. This work addresses the cellular and molecular mechanisms underlying craniofacial anomalies; over 700 distinct craniofacial syndromes have been described, with most attributed to neural crest cell developmental defects.

Performance occurs at the Stowers Institute for Medical Research in Kansas City, Missouri. The period of performance runs from September 1, 2026, through August 31, 2028. The award is structured as a Project Grant, a form of assistance funding that supports discrete research projects under NIH peer review.

Abstract

One third of all congenital anomalies affect structures in the head and face, and to date, more than 700 distinct craniofacial syndromes have been described. The majority of the cartilage, bone and connective tissue in the head and face, as well as sensory ganglia, dental pulp and pigment cells are derived from neural crest cells (NCC), a stem and progenitor cell population formed during early embryogenesis. Most craniofacial disorders are attributed to defects in NCC development, hence, there is a critical need to understand the cellular and molecular mechanisms that dictate NCC development during craniofacial morphogenesis and identify etiological factors driving pathogenicity. Recent work from the trainor lab demonstrated that RNA polymerase i (POL i)- mediated ribosomal RNA (rrna) transcription, which is the rate limiting step in ribosome biogenesis, is elevated in nccs compared to other cell types. In support of this idea, NCC-specific disruption of POL i function in early stages of NCC development leads to increased NCC death and craniofacial anomalies characteristic of congenital craniofacial disorders like treacher collins syndrome. Additionally, evidence from other studies supports elevated requirements for ribosomes and translational capacity in order for stem cells to acquire new fates, suggesting that ribosome biogenesis also plays a critical role during the differentiation stage of NCC development. From this collective evidence, i hypothesize that increased rrna transcription and ribosome biogenesis are essential for NCC fate acquisition and differentiation during craniofacial development. To test this hypothesis, i will globally delete POLR1A, which forms the catalytic core of POL i, in a temporal fashion in mice and examine effects on cartilage, bone and sensory neuron progenitors. In parallel, i will investigate the consequences of POL i loss-of-function on pluripotent ipscs and multipotent nccs during their differentiation. These in vivo and in vitro models will be examined further using multiomic approaches to identify the molecular mechanism driving pathogenicity upon POL i and ribosome biogenesis disruption. For the R00 portion of this project, i will define the requirement for distinct POL i proteins during craniofacial development by generating zebrafish mutants for all POL i-specific subunits that lack animal models. The expected overall impact of this innovative proposal is that IT will advance our mechanistic understanding of how disruptions in ribosome biogenesis during craniofacial development can affect specific cell types, which has broad implications for ribosomopathies in general, and human health.