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Researchers Identify Clue to Asymmetric Cell Division

Phosphorylation of a surface protein on endosomes is key to the organelles’ uneven distribution in daughter cells.

Sep 1, 2017
Shawna Williams

EDITOR'S CHOICE IN CELL BIOLOGY

During cell division in fruit flies’ sensory organ precursor cells, microtubules draw endosomes with the Sara protein on their surface to the central spindle. There, Sara is phosphorylated, causing the endosomes to detach from the spindle and travel to one side of the mother cell, with most of them moving into the daughter cell known as pIIa, where microtubule disassembly is greater. That cell divides again to form the outer shaft and socket of a hair on the fly’s back, while its sibling, pIIb, gives rise to the hair’s inner sheath and neuron. Without Sara, hair formation is compromised.THE SCIENTIST STAFF
S. Loubéry et al., “Sara phosphorylation state controls the dispatch of endosomes from the central spindle during asymmetric division,” Nat Commun, 8:15285, 2017.

Central to normal development are steps in which stem or progenitor cells divide asymmetrically to form daughters with different fates. But what determines these divergent paths? A recent study by Marcos Gonzalez-Gaitan and colleagues at the University of Geneva found that phosphorylation is key to preferentially directing certain cellular vesicles called endosomes to one of the daughter cells, enabling asymmetric division.

To study asymmetrical cell division, many researchers look to the sensory organ precursor cells (SOPs) that form hairs on the backs of fruit flies in a series of three cell-division steps. First, an SOP divides asymmetrically into cells known as pIIa and pIIb. The pIIa cell then divides again to form an outer hair cell and a socket, while pIIb divides twice more, ultimately producing a neuron and its sheath.

Gonzalez-Gaitan’s group had previously found that while most endosomes are split evenly between the two daughter cells during asymmetric cell division, those that contain signaling molecules Notch and Delta and have a surface protein called Sara mainly end up in pIIa. Prior to that, the Sara endosomes are ferried along microtubules to a structure in the middle of the dividing cell known as the central spindle. But it remained unclear how the endosomes were able to break free of the spindle and begin their migration toward the side of the mother cell that becomes pIIa.

To decipher this part of the process, the group used immunoprecipitation to suss out factors that interact with Sara. The researchers found that a phosphatase was interacting with Sara, and that “on Sara there are three sites of possible phosphorylation,” says Alicia Daeden, a graduate student in Gonzalez-Gaitan’s lab. Further experiments revealed that Sara’s phosphorylation state dictated the Sara endosomes’ asymmetric distribution, with about 80 percent going into the pIIa cell, she says. When the team generated mutants that had only one wild-type version of Sara, and thus less of the functional protein, the Sara endosomes were distributed more evenly—closer to a 60/40 distribution between the daughter cells—and the flies’ backs were nearly bald.

Matilde Cañelles López, who studies lymphocyte development in mice at the Institute of Parasitology and Biomedicine López-Neyra in Granada, Spain, says Gonzalez-Gaitan’s group managed to “very nicely see in living cells how the endosomes move and go into one cell,” causing the daughter cells to take different paths. The results dovetail with a hypothesis her own group developed based on their work with knockout mice, she says: that asymmetric distribution of endosomes during cell division is key to development.

“It’s easy to start speculating that something like loss of this function could, for example, cause some of the tissues to become tumor prone,” says Pekka Katajisto, a stem cell biologist at the University of Helsinki, if aberrant divisions result in two stem cells instead of one stem cell and one differentiated cell. However, he adds, the results likely don’t apply directly to mammals, which lack the Sara protein.

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