Research Associate Professor
Laboratory of Molecular Neuro-oncology
Darnell is a leading authority on fragile X syndrome, the most common monogenic cause of intellectual disability and autism. Fragile X is usually caused by the loss of an RNA-binding protein, FMRP. However, two patients have been identified with missense mutations that occur in FMRP’s RNA-binding domains. By reproducing one mutation in mice, Darnell confirmed that the mutation causes fragile X symptoms due to loss of function of the RNA-binding domain in translational control, and provided a new mouse model for the field.
Darnell applied a new technique developed in the lab to determine the set of mRNAs that FMRP binds. The technique, called CLIP-Seq, provides an unbiased snapshot of where FMRP binds RNA across the transcriptome in living cells. Darnell found that FMRP binds to mRNAs encoding many important synaptic proteins as well as chromatin regulatory enzymes and transcription factors. These categories of FMRP-regulated genes have a high overlap with candidate genes for autism spectrum disorders and schizophrenia. Darnell is now extending the CLIP-Seq studies to single neuronal cell types using a new mouse model that she and her colleagues developed in which endogenous FMRP can be conditionally tagged for CLIP-Seq experiments.
To understand the function of FMRP in translational control, Darnell developed a unique translation assay designed to preserve endogenous FMRP–RNA interactions in the brain, and showed that FMRP inhibits the translation of the same mRNAs in association with stalled ribosomes. Darnell is now working to determine whether FMRP stalls ribosomes or stabilizes ribosomes stalled by something else. Uncovering why and how FMRP accomplishes this, as well as how this translational repression is relieved, is an area of great interest in her work.
Darnell’s work is furthering our understanding of how FMRP regulates mRNA translation important for normal synaptic function, and is opening new avenues for therapy based on a deeper understanding of FMRP’s function.