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Developmental biology - Brain Development|
Egg Inability to Create Large Proteins Affects Brain
The transcription from DNA to RNA and translation of RNA into proteins - occurs in rapid succession. However, in some highly specialized cells, such as neurons and eggs, RNA is created and then stored for future use.
Previous research suggested that Fmr1 prevents stored RNA molecules from overproducing new proteins. But many of these studies were done using brain cells, and results are very complicated to analyze. Greenblatt and Spradling decided to solve the problem by studying the effects of Fmr1 on the protein-manufacturing process in a much simpler cell type - fruit fly eggs.
Alan Spradling explains: "Our results surprised us. We found that egg cells lacking Fmr1 were at first completely normal. But if they were stored, they lost function much faster than stored eggs with normal Fmr1. This is reminiscent of the human ovarian failure syndrome. What's more, when fertilized, these Fmr1-lacking eggs created offspring with severe nervous system defects, reminiscent of fragile X syndrome."
Expanding their analysis, Greenblatt and Spradling found that Fmr1 mutant egg cells produce reduced amounts of several hundred proteins, many of which, if missing completely, are associated with autism.
"We think that Fmr1 serves as a sort of a helper, which boosts production of critically important large proteins that are difficult for eggs or neurons to manufacture," Greenblatt adds. "Without Fmr1, egg cells have inadequate supplies of specific large proteins and prematurely start to fail. Since Fmr1 is also important in the brain, the loss of certain large proteins associated with autism could explain the autism-like symptoms of fragile X syndrome patients."
Future research should investigate whether problems related to the manufacture of large proteins is linked to aging or other disorders such as Alzheimer's disease and ALS.
Mutations in the fragile X mental retardation 1 gene (FMR1) cause the most common inherited human autism spectrum disorder. FMR1 influences messenger RNA (mRNA) translation, but identifying functional targets has been difficult. We analyzed quiescent Drosophila oocytes, which, like neural synapses, depend heavily on translating stored mRNA. Ribosome profiling revealed that FMR1 enhances rather than represses the translation of mRNAs that overlap previously identified FMR1 targets, and acts preferentially on large proteins. Human homologs of at least 20 targets are associated with dominant intellectual disability, and 30 others with recessive neurodevelopmental dysfunction. Stored oocytes lacking FMR1 usually generate embryos with severe neural defects, unlike stored wild-type oocytes, which suggests that translation of multiple large proteins by stored mRNAs is defective in fragile X syndrome and possibly other autism spectrum disorders.
Fragile X and fragile translation in flies
Mutations in the fragile X mental retardation 1 (FMR1) gene underlie fragile X syndrome and fragile X–associated primary ovarian insufficiency, which are prominent intellectual disability and reproductive disorders, respectively. FMR1 is thought to reduce protein synthesis (translation) at synapses. In Drosophila oocytes, Greenblatt and Spradling found that Fmr1 loss leads to oocytes that generate embryos exhibiting neural defects (see the Perspective by Aryal and Klann). Ribosome profiling of oocytes identified a specific role for FMR1 in enhancing the translation of large proteins, including many associated with autism. FMR1 seems to help maintain translation of large mRNAs that otherwise condense into inactive ribonucleoprotein particles. This mechanism may underlie other causes of autism and mental dysfunction.
Authors: Ethan J. Greenblatt, Allan C. Spradling
The authors declare no competing financial interests.
This research was funded by the Jane Coffin Childs Memorial Fund and the Howard Hughes Medical Institute.
The Carnegie Institution for Science is a private, nonprofit organization headquartered in Washington, D.C., with six research departments throughout the U.S. Since its founding in 1902, the Carnegie Institution has been a pioneering force in basic scientific research. Carnegie scientists are leaders in plant biology, developmental biology, astronomy, materials science, global ecology, and Earth and planetary science.
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Fragile X-associated disorders encompass several conditions caused by expansion mutations in the fragile X mental retardation 1 (FMR1) gene. The learning disability in fragile X syndrome results from >200 CGG/CCG repeats in exon 1 of the X-linked gene FMR1. Image Credit: Ethan J. Greenblatt, Allan C. Spradling SCIENCE (2018)