Replicating intellectual disability

SAN DIEGO—Researchers at the University of California San Diego School of Medicine have developed the first mice that lack the Upf3b gene, providing a new model for studying its underlying role in intellectual disabilities and neurodevelopmental disorders. The study was published Sept. 26 in Molecular Psychiatry.

In humans, mutations in the UPF3B gene cause intellectual disabilities and are strongly associated with autism spectrum disorder, attention deficit hyperactivity disorder and schizophrenia. This gene plays a role in nonsense-mediated RNA decay (NMD), a supervisory system cells use as “volume control” on many genes.

“These observations about UPF3B made us wonder if NMD is important for mammalian brain development,” said senior author Dr. Miles Wilkinson, a professor of reproductive medicine at the university’s medical school.

NMD acts on messenger RNAs (mRNAs) and was initially thought to serve only as a quality control mechanism in that it degraded irregular mRNAs that encode potentially harmful proteins. But it has more recently become clear, the university notes, that NMD also degrades normal mRNAs in specific cell types and situations when they are not needed.

Wilkinson’s team found that Upf3b-deficient mice differed from normal mice in a number of cellular and behavioral ways. For example, their neural stem cells were impaired in their ability to specialize into functional neurons. The neurons they did have were deficient in their ability to form dendrites and dendritic spines, structures critical for neuron-neuron communication. These Upf3b-deficient mice also exhibited defects in a specific form of memory and learning related to fear, and they were defective in sensory processing in a way often associated with schizophrenia and other brain disorders.