Research Associate Professor
Laboratory of Molecular Neuro-oncology
Dr. Darnell is a leading authority on fragile X syndrome (FXS), the most common cause of inherited intellectual disability and the most common monogenic cause of autism. FXS is usually caused by the loss of expression of an RNA-binding protein, the fragile X mental retardation protein (FMRP). However, one patient has been identified with a mutation in one of FMRP’s RNA-binding domains. By reproducing this mutation in mice, Dr. Darnell proved that the mutation causes fragile X symptoms. It prevents the protein from binding RNA in neurons and carrying out its normal functions controlling translation of messenger RNA into protein. Dr. Darnell works to understand the set of RNAs that FMRP binds to and how it affects the translation of these messenger RNAs into proteins that are important for synapse formation and function.
Dr. Darnell has recently applied a new technique to study FMRP’s role in normal neurological function. The technique, called high throughput sequencing cross-linking immunoprecipitation (HITS-CLIP), provides an unbiased snapshot of where FMRP binds to RNA across the entire genome in living cells. Using HITS-CLIP, Dr. Darnell discovered that FMRP binds to messenger RNAs encoding many important synaptic proteins. She developed a unique translation assay designed to preserve endogenous FMRP-RNA interactions from the brain and showed that FMRP inhibits the translation of these same messenger RNAs by stalling ribosomes.
Dr. Darnell is now extending these studies to FMRP-RNA interactions in single cell types using a new mouse in which FMRP can be conditionally tagged for HITS-CLIP experiments. The work is furthering an understanding of how FMRP regulates messenger RNA translation important for normal synaptic function and is opening new avenues for therapy based on a deeper understanding of FMRP’s function.