Fragile X syndrome is the most common inherited intellectual disability in children, and it sometimes co-occurs with autism. In a study published today in Cell Reports, researchers discovered how the genetic defect in fragile X syndrome delays production of neurons at a critical time in the embryo’s brain development. The researchers also describe a previously unknown regulatory mechanism that controls the differentiation of stem cell into neurons.
“During embryonic brain development, the right neurons have to be produced at the right time and in the right numbers,” says senior author Yongchao Ma of Northwestern University. “We focused on what happens in the stem cells that leads 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.”
Fragile X syndrome is caused by a mutation in a gene called FMR1 that encodes the FMRP protein. Previously, the function of FMRP protein during early brain development was not known. While other studies in fragile X development have focused on the interactions between mature neurons, the present study is the first to offer a new understanding of the disease at a stem cell level.
Dr. Ma and colleagues discovered that within a stem cell, FMRP plays a key role as a “reader” of a chemical tag (m6A) on the RNA. This tag carries instructions on how to process the RNA. By reading these instructions, FMRP exports the RNAs from the nucleus to the cytoplasm of cells where the m6A-tagged RNAs will become proteins that control the differentiation of stem cells into neurons.
“We show 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,” says first author Brittany Edens of Northwestern University.
According to Ma, gene therapy may be a possibility in the future to treat fragile X syndrome. “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 says.