Mutations in the Ankle2 gene can impair brain development. The larval fly brain on the left comes from a healthy animal, with neurons highlighted in green and neuroblasts highlighted in purple. The much-smaller brain on the right comes from a fly with no functioning copy of Ankle2.Credit: N. Link et al./Developmental Cell 2019

Patients with rare genetic mutations are helping scientists understand exactly how Zika virus harms developing brains.

By replicating human patients’ mutations in flies, researchers have uncovered one way that Zika virus leads to microcephaly, a congenital condition resulting in a smaller-than-normal head and developmental delays. The new work, published November 14, 2019, in the journal Developmental Cell, identifies a set of genes involved in microcephaly. One of these genes codes for a protein that’s targeted during Zika virus infection.

In the future, a drug that protects this protein could quell Zika’s damaging developmental effects, says study coauthor Hugo Bellen, a Howard Hughes Medical Institute Investigator at Baylor College of Medicine.

Zika virus is transmitted by mosquitoes and, in healthy adults, generally causes mild symptoms. But when pregnant women are infected, the virus can have lifelong consequences for the fetus, including developmental abnormalities like microcephaly. Zika, previously a rare disease, became an international concern during a large outbreak that began in 2015.

“What’s interesting is that this set of genes was known in flies for more than 15 years and was never associated with microcephaly.”

Hugo Bellen

Bellen and his colleagues didn’t set out to study Zika. In the course of a larger project, his team noticed that flies with a mutation in a gene called Ankle2 ended up with smaller-than-usual brains – a Drosophila manifestation of microcephaly. Then, in a database of patients with rare genetic mutations, they found patients with Ankle2 mutations who had severe cases of microcephaly from unknown causes. That was a sign that Ankle2 mutations might be relevant in human diseases that affect brain development, says study coauthor Nichole Link, a geneticist and developmental biologist in Bellen’s lab.

To figure out how Ankle2 mutations were influencing brain formation, the researchers went back to flies. Normally, Ankle2 works with a series of other genes to control the division of neuroblasts, stem cells that give rise to neurons. These cells are crucial for proper brain development. Mutations in the Ankle2 gene, though, messed with neuroblast division. Larval flies with the mutation had fewer neuroblasts and smaller-than-expected brains.

“What’s interesting is that this set of genes was known in flies for more than 15 years and was never associated with microcephaly,” says Bellen.

Now, though, these genes have new relevance. Last year, Bellen’s team, working with Nevan Krogan’s team at the University of California, San Francisco, identified a protein produced during Zika virus infection that blocks the proper activity of the Ankle2 protein. In the new work, the researchers have shown in more detail how that interaction harms brain development – by preventing neuroblasts from dividing correctly.

The find is part of a bigger initiative between Bellen’s lab and other scientists at Baylor and beyond, in which researchers use flies to study mutations found in patients with undiagnosed diseases. The work can help scientists learn more about an individual mutation’s functional effects. And sometimes, as with microcephaly caused by Zika, a rare mutation can illuminate the mechanism of a more common disease, Link says.

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Citation

Nichole Link et al. “Mutations in ANKLE2, a ZIKA Virus Target, Disrupt an Asymmetric Cell Division Pathway in Drosophila Neuroblasts to Cause Microcephaly.” Developmental Cell, published online November 14, 2019. doi: 10.1016/j.devcel.2019.10.009

This paper was originally published as a preprint on bioRxiv.