Lower levels of the FMRP protein in neural stem cells delay their conversion into neurons during brain development by disrupting the transport of RNA molecules, new research shows. Scientists say those decreased FMRP levels are likely linked to impaired learning and behavior in fragile X syndrome.
These findings reveal new treatment targets, and suggest the potential for gene therapy in fragile X, according to the scientists.
The study, “FMRP Modulates Neural Differentiation through m6A-Dependent mRNA Nuclear Export,” appeared in the journal Cell Reports.
Fragile X — the most common genetic cause of autism and intellectual disability — results from a faulty gene called FMR1, which leads to decreased levels of the FMRP protein. Although its function is only partially known, this cellular protein — found both in and outside the nucleus — has been associated with brain and nerve cell development. Researchers say reduced levels of FMRP are likely associated with the impaired learning and behavior in people with fragile X.
The FMRP protein can read a chemical tag, called m6A, present in messenger RNA (mRNA) molecules within stem cells. mRNA is the intermediate molecule that is produced after DNA is processed and before a protein is produced. The m6A carries instructions on how to correctly process mRNA, and has been increasingly implicated in RNA metabolism and function. It has a role in the differentiation of neural stem cells and in learning.
To further understand the function of the FMRP protein during early brain development, researchers examined a mouse model that was missing the Fmr1 gene. They found that lower levels of the FMRP protein delay the differentiation of neural progenitor cells — those that give rise to neurons. This mimics what was in seen in another type of genetically modified mouse, one that lacks the Mettl14 gene and does not have the m6A modification normally present in mRNA molecules.
In both types of genetically modified, or transgenic mice, FMRP’s target mRNAs — those that would be “read” by the FMRP protein — were retained in the cell’s nucleus. That disrupted their transport to the cell cytoplasm, and their role in nerve cell differentiation after birth.
The team also found that the FMRP protein preferentially binds RNAs with the m6A modification, and works with another protein, called CRM1, to induce their transport out of the nucleus.
Delivering wild-type, or normal FMRP protein to neural progenitor cells lessened the mRNA transport defect, “establishing a critical role for FMRP in mediating m6A-dependent mRNA nuclear export during neural differentiation,” the investigators said. This “may contribute to functional deficits in [fragile X],” they added.
“During embryonic brain development, the right neurons have to be produced at the right time and in the right numbers,” Yongchao Ma, PhD, the study’s senior author and a researcher at the Ann & Robert H. Lurie Children’s Hospital of Chicago, said in a press release.
“Our discoveries shed light on the earliest stages of disease development and offer novel targets for potential treatments,” added Ma, also a professor of pediatrics, neurology and physiology at Northwestern University Feinberg School of Medicine.
Brittany Edens, the study’s first author, said the results “also expand understanding of how the flow of genetic information form DNA to RNA to protein is regulated, which is a central question in biology.”
Work in this field now focuses on how to boost FMRP protein activity in stem cells “to correct the timing of neuron production and ensure that the correct amount and types of neurons are available to the developing brain,” added Ma. “There may be potential for gene therapy for [fragile X].”