Fragile X syndrome is a leading genetic cause of autism, as roughly one in three individuals with the syndrome also have autism. Moreover, mutations in the gene that causes fragile X syndrome, FMR1, accounts for up to 5% of autism cases. Due to this inextricable link, research on fragile X can provide invaluable insights into the development of autism, as well as other neurodevelopment disorders. Now, investigators from Northwestern University’s Feinberg School of Medicine and the Ann & Robert H. Lurie Children’s Hospital of Chicago discovered how the genetic defect in fragile X delays production of neurons at a critical time during embryonic brain development.
Findings from the new study—published recently in Cell Reports through an article titled “FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export”—describes a previously unknown regulatory mechanism controlling how stem cells differentiate into neurons. Furthermore, the research team identified early disruptions in this process for fragile X syndrome, the most common inherited intellectual disability in children.
“During embryonic brain development, the right neurons have to be produced at the right time and in the right numbers,” explained senior study investigator Yongchao Ma, PhD, a researcher at Lurie Children’s, as well as associate professor at the Feinberg School of Medicine. “We focused on what happens in the stem cells that lead to slower production of neurons that are responsible for brain functions including learning and memory. Our discoveries shed light on the earliest stages of disease development and offer novel targets for potential treatments.”
Additional studies in fragile X development have focused on the interactions between mature neurons. Ma’s study is the first to offer a new understanding of the disease at a stem cell level.
Fragile X syndrome occurs in approximately 1 in 4,000 males and 1 in 8,000 females and is caused by a mutation in the gene called FMR1 that encodes a protein called FMRP. The genetic defect leads to reduced FMRP protein levels. Previously the function of FMRP protein during early brain development was not known.
Amazingly, however, the research team discovered that within a stem cell, the FMRP protein plays a key role as a “reader” of a chemical tag (called m6A) on the RNA. This tag carries instructions on how to process the RNA.
“We showed that fragile X mental retardation protein (FMRP) reads m6A to promote nuclear export of methylated mRNA targets during neural differentiation,” the authors wrote. “Fmr1 knockout (KO) mice show delayed neural progenitor cell cycle progression and extended maintenance of proliferating neural progenitors into postnatal stages, phenocopying methyltransferase Mettl14 conditional KO (cKO) mice that have no m6A modification. RNA-seq and m6A-seq reveal that both Mettl14cKO and Fmr1KO lead to the nuclear retention of m6A-modified FMRP target mRNAs regulating neural differentiation, indicating that both m6A and FMRP are required for the nuclear export of methylated target mRNAs.”
By reading these instructions, FMRP protein exports the RNAs from the nucleus to the cytoplasm of cells where the m6A-tagged RNAs will become proteins that control stem cell differentiation into neurons.
“We showed how the reduced amount of FMRP protein in neural stem cell results in decreased nuclear export of m6A-tagged RNAs and ultimately, slower production of the neurons that are essential for healthy brain development,” noted lead study investigator Brittany Edens, a graduate student in the Northwestern University interdepartmental neuroscience program who works in Ma’s lab. “Our findings also expand understanding of how the flow of genetic information from DNA to RNA to protein is regulated, which is a central question in biology.”
“Currently we are exploring how to stimulate FMRP protein activity in the stem cell, in order to correct the timing of neuron production and ensure that the correct amount and types of neurons are available to the developing brain,” Ma concluded. “There may be potential for gene therapy for fragile X syndrome.”