New insights into cellular 'bridges' shed light on development, disease

In a new study, Yale researchers uncover for the first time how it is that germ cells in fruit flies form these ring canals, a finding that they say will provide new insights into a widely shared feature of development and into diseases in which cell division is disrupted.

The findings were published March 9 in Developmental Cell.

Scientists have observed ring canals in male and female germ cells across all types of species, from simpler organisms like sponges and fruit flies to more complex animals like mice and humans. And while their purpose is not fully understood, there is evidence that ring canals are important for cell development, the researchers say.

"For example, in female fruit flies, ring canals are required to grow a functional oocyte, a developing egg cell," said Lynn Cooley, the C.N.H. Long Professor of Genetics at Yale School of Medicine and senior author of the new study. "If you block ring canals, female flies grow tiny, little eggs and can't reproduce."

But how ring canals form has remained unclear.

To better understand their formation, the researchers used a live imaging approach. They tagged several ring canal proteins in fruit flies with florescent molecules and, using a microscope, observed what those proteins did over time in the germ cells of both males and females.

"When we did this, we saw the first signs of a structure we call the germline midbody," said Kari Price, a postdoctoral fellow in Cooley's lab and lead author of the study.

The midbody is a structure that forms during cell division and one of its roles is to recruit the molecules needed to sever cells at the end of the process. In the study, the researchers found that an unusually large midbody formed in fruit fly germ cells, stuck around for about 20 to 30 minutes, and then, instead of initiating full separation, underwent dramatic remodeling from a sphere into a ring. These midbody rings then became stable ring canals that connected the sibling cells.

The researchers also found this midbody-to-ring canal transition in fresh-water polyps and mice, suggesting it's a feature that has been preserved throughout evolution.

"To see this solid, little object turn into a ring -- that had not been observed in intact living cells before. It was, to us, very striking; it was an 'a-ha moment,'" said Cooley. "And it would've been tough to discover this in anything other than fruit flies. This study is such a great example of how model systems like fruit flies are essential for understanding fundamental mechanisms of development."

In addition to being an important step toward understanding the function and formation of ring canals, the researchers say, the new discovery may also yield insight into incomplete cell division that occurs in typical development across a variety of species and into diseases where incomplete cell division is implicated, such as colorectal cancer, Hodgkin's lymphoma, and some immunodeficiency syndromes.

The findings may also help scientists understand the very beginnings of evolution.

"There are very primitive creatures that, when they divide, make colonies that are attached with persistent cellular bridges, much like what we see with germ cells," said Cooley. "Maybe this way of keeping sibling cells connected in a colony or cluster is the beginning of how multicellular evolution occurred, and maybe germ cells are a reflection of that."

Going forward, the researchers aim to identify the mechanisms that drive germ cells to remain connected.

"In this current study we saw that blocking an enzyme called Citron kinase delayed or prevented the midbody-to-ring canal transition," said Price. "So we're looking at Citron kinase more deeply to see what exactly it's doing in these cells during division."