How Clock Genes Drive Healthy Spinal Formation

Published December 2020 | Nature

When healthy, the vertebrae of developing zebrafish project a regimented, evenly spaced set of spines. This outcome depends heavily on sets of co-expressed genes working in concert, like clocks.

Now it appears that achieving balanced outcomes also can require that key clock genes be located in close proximity, not just functioning at the same time, according to research led by first author Oriana Zinani, PhD, and senior author Ertugrul Ozbudak, PhD.

In zebrafish, the team used CRISPR-Cas9 to disrupt a paired gene set known to play a role in spine formation: her1 and her7. They tracked the effects using single-cell transcript counting, real-time imaging, and computational modeling. The transparent embryos of zebrafish made them an ideal model for observing how their skeletons formed.

Normally, the her1 and her7 genes are expressed on the same chromosome. When functional genes are on different homologous chromosomes, the more likely the zebrafish became to develop misshaped vertebrae with irregularly protruding spines- even though the genes themselves remained functional.

The team found that embryos developing in unusually cold water exhibited similar dysfunctions, suggesting that environmental stresses can interfere with development by scattering closely paired genes. The team also reports that gene pair co-location is a commonly seen process for many paired genes in humans and may be at work in other conditions, such as developmental disorders and some cancers.

“We anticipate gene pairing is similarly advantageous in other systems, and could enable engineering of precise synthetic clocks in embryos and organoids,” Ozbudak says.

Since publication in Nature, the research team also has published a review in Trends in Genetics, highlighting widespread gene pairing and clustering of co-expressed genes across organisms.

Ozbudak plans to present more findings at upcoming Gordon Research Conference and Keystone Symposium.

How Gene Pairing Affects Spine Development

Gene-paired embryos, showing typical vertebrae development and genes her1 and her7, unpaired, showing vertebral variations.