The blood-brain barrier (BBB) is a vital layer of protective cells around the brain and spinal cord. Understanding how the barrier works to allow in or keep out certain substances has critical implications for disease progression to drug delivery. Now, working with mice and zebrafish, researchers from Harvard Medical School (HMS) report they have identified a gene expressed in neurons that produces a signal needed for the development and maintenance of the blood-brain barrier. The findings could help scientists control the blood-brain barrier, which can help deliver drugs into the central nervous system or counter damage from neurodegenerative disease.

The new study is published in Developmental Cell in an article titled, “The secreted neuronal signal Spock1 promotes blood-brain barrier development.”

“The BBB is a unique set of properties of the brain vasculature which severely restrict its permeability to proteins and small molecules,” the researchers wrote. “Classic chick-quail chimera studies have shown that these properties are not intrinsic to the brain vasculature but rather are induced by surrounding neural tissue. Here, we identify Spock1 as a candidate neuronal signal for regulating BBB permeability in zebrafish and mice.”

“In normal, day-to-day life, you need a blood-brain barrier to help protect you from invading toxins and pathogens in the blood,” explained lead author Natasha O’Brown, PhD, a research fellow in systems biology at HMS who is starting her lab at Rutgers University in September.

O’Brown was studying a gene called mfsd2aa that, when mutated, causes the blood-brain barrier in zebrafish to become leaky throughout the entire brain. However, she noticed that some zebrafish had a barrier that was permeable in the forebrain and midbrain, but intact in the hindbrain.

“This observation led me down a rabbit hole of finding the gene that causes the blood-brain barrier to become regionally permeable,” she said.

O’Brown conducted genetic screens on the zebrafish and discovered that the region-specific breakdown of the barrier was linked to a mutation in spock1.

The researchers confirmed that a spock1 mutation caused the blood-brain barrier to become permeable in some areas but not others. They also observed that spock1 was expressed in neurons throughout the retina, brain, and spinal cord, but not in the cells that make up the barrier itself.

“Spock1 is a potent secreted neural signal that is able to promote and induce barrier properties in these blood vessels; without it, you don’t get a functional blood-brain barrier,” O’Brown said. “It’s like a spark on a gas stove, providing a cue that tells the barrier program to turn on.”

O’Brown now wants to explore how different lineages of pericytes in the barrier are differentially affected by spock1 signaling. She would also like to test out stroke models, to see if administering spock1 can counter a stroke’s effects on the blood-brain barrier.

“This isn’t the first neural signal scientists have found, but it is the first signal from neurons that specifically seems to regulate barrier properties,” O’Brown said. “I think this makes it a potent tool to try and toggle the switch.”

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