Soon after fertilization, the cells in an embryo, which have been dividing furiously from the start, begin to take on different forms and to separate into layers that will eventually give rise to the organism’s various tissues and organs. But dividing and changing shape, two distinct processes, cannot happen simultaneously. Directing activities so each takes place in turn becomes critical when the pressure is on to do both. A team of Weizmann Institute scientists recently found how a cellular “traffic cop” temporarily halts cell division so other processes can proceed.
In an article published in Current Biology, Prof. Talila Volk of the Weizmann Institute’s Molecular Genetics Department has revealed a series of interactions between proteins that serves to maintain order in the early stages of embryonic development. The “cop” is a fruit fly protein named HOW, and it works by “arresting” strands of RNA on their way to manufacture a second protein. Levels of the second protein, known as Cdc25, regulate the timing of cell division, and its production is ultimately controlled by yet another protein, Twist, which sets the process in motion. In this intricately choreographed scenario, cells invaginate from the outer layer of the nascent embryo into its interior, changing shape as they go. These cells form the mesoderm or “in-between layer,” which eventually gives rise to muscle and other internal tissues. At the same time, Twist prompts the Cdc25 gene to step up activity, as well as activating the production of HOW. HOW then takes direct action against Cdc25 RNA by breaking it apart, leading to the arrest of cell division during mesoderm invagination.
When Volk and her team studied the newly-formed embryos of mutant fruit flies that lacked the gene for HOW, they found the timing for this early developmental stage was skewed. Cells divided to excess while the inward migration of the mesoderm-bound cells was delayed.
Once mesoderm formation is complete, its cells undergo a new wave of division. The scientists suggest this happens because HOW’s arrest-and-destroy tactics delay Cdc25 activity, rather than stop it, altogether. Some of the RNA escapes detection by HOW, causing Cdc25 levels to rise very slowly. With carefully timed coordination, Cdc25 reaches critical levels for instigating cell division just when cells have finished changing shaped and are settled into place.
Volk and her team believe HOW may have several important functions in regulating further development in the fruit fly mesoderm. Other, similar proteins are active in various developing embryos, including one in mammals known to regulate nerve insulation and myelin formation in the central and peripheral nervous system. All commonly target RNA, shooting the messenger rather silencing the message at its source (the DNA), as many other regulatory proteins do. This may give them a relatively quick response time, helping the cell to efficiently fine-tune the complex ordering of development.
Prof. Talila Volk’s research is supported by the Leo and Julia Forchheimer Center for Molecular Genetics. Prof. Volk is the incumbent of the Professor Sir Ernst B. Chain Professorial Chair of Neuro-Immunology.