A UCLA-led study reveals a new role for a gene that’s associated with autism spectrum disorder, intellectual disability and language impairment.
The gene, Foxp1, has previously been studied for its function in the neurons of the developing brain. But the new study reveals that it’s also important in a group of brain stem cells — the precursors to mature neurons.
Mutations in Foxp1 were first identified in patients with autism and language impairments more than a decade ago. During embryonic development, the protein plays a broad role in controlling the activity of many other genes related to blood, lung, heart, brain and spinal cord development. To study how Foxp1 mutations might cause autism, researchers have typically analyzed its role in the brain’s neurons.
In the new study, published in Cell Reports, researchers monitored levels of Foxp1 in the brains of developing mouse embryos. They found that, in normally developing animals, the gene was active far earlier than previous studies have indicated — during the period when neural stem cells known as apical radial glia were just beginning to expand in numbers and generate a subset of brain cells found deep within the developing brain.
When mice lacked Foxp1, however, there were fewer apical radial glia at early stages of brain development, as well as fewer of the deep brain cells they normally produce. When levels of Foxp1 were above normal, the researchers observed more apical radial glia and an excess of those deep brain cells that appear early in development. In addition, continued high levels of Foxp1 at later stages of embryonic development led to unusual patterns of apical radial glia production of deep-layer neurons even after the mice were born.
Some people have mutations in the Foxp1 gene that blunt the activity of the Foxp1 protein, while others have mutations that change the protein’s structure or make it hyperactive.
The researchers also found intriguing hints that Foxp1 might be important for a property specific to the developing human brain. They also examined human brain tissue and discovered that Foxp1 is present not only in apical radial glia, as was seen in mice, but also in a second group of neural stem cells called basal radial glia.
Basal radial glia are abundant in the developing human brain, but absent or sparse in the brains of many other animals, including mice. However, when scientists elevated Foxp1 function in the brains of mice, cells resembling basal radial glia were formed. The scientists hypothesized that basal radial glia also are connected to the size of the human brain cortex: Their presence in large quantities in the human brain may help explain why it is disproportionately larger than those of other animals.