RNAs Pivotal Roles in Brain Development
by Nicole Giese Rura
Whitehead Institute scientists have identified that lincRNAs (long intervening non-coding RNAs) play a key role during embryo brain development in zebrafish. They also found that human versions of lincRNAs can substitute for missing or damaged zebrafish versions, impling that non-coding RNAs have been retained in humans as well as fish.
Until now, lincRNAs have been studied primarily in cell lines rather than at the organ level, which has eliminated research into how lincRNAs affect growth and development.
“These studies show that zebrafish, an animal that is frequently used to study the genetics of animal development, can also serve as a tool to uncover in systematic fashion the functions of lincRNAs,” says Whitehead Member David Bartel, who is also a Howard Hughes Medical Institute investigator and a professor of biology at MIT.
“This is another case in which a phenomenon in zebrafish provides insight into what’s probably happening in humans, as has been established in many studies of protein-coding genes.”
“These studies show that zebrafish, an animal that is frequently used to study the genetics of animal development, can also serve as a tool to uncover in systematic fashion the functions of lincRNAs,” says Whitehead Member David Bartel. “This is another case in which a phenomenon in zebrafish provides insight into what’s probably happening in humans, as has been established in many studies of protein-coding genes.”
Despite their prevalence in the cell, lincRNAs have been referred to as the “dark matter” of all the transcribed RNAs because little is known of their functions or mechanisms. One limitation to studying this class of RNAs is their low similarity between species. Unlike protein-coding genes, which are frequently well-conserved between species, lincRNA genes typically have a very small bit of conserved DNA between species, if any.
For example, Bartel lab scientists Igor Ulitsky and Alena Shkumatava identified more than 500 lincRNAs in zebrafish but found that only 29 of these have homologs in both humans and mice.
Ulitsky and Shkumatava tested the function of two of the 29. Both had striking effects on the zebrafish’s brain development. Reduction of one of the lincRNAs, called cyrano, caused the zebrafish to have enlarged snouts, small heads and eyes, and short, curly tails. The zebrafish lacking the other lincRNA, called megamind, had abnormally shaped heads and enlarged brain ventricles.
To test if the human homologs of the cyrano and megamind lincRNAs were functionally equivalent, Shkumatava injected the human versions into the damaged zebrafish. Remarkably, the human lincRNAs rescued the zebrafish and restored brain development and head size for both lincRNAs, indicating that the human lincRNAs may have the same role in embryo development as their zebrafish analogs.
“This work represents a major advance because it provides a framework for studying lincRNAs, a poorly understood, but abundant class of molecules,” says Michael Bender, who oversees RNA processing and function grants at the National Institutes of Health’s National Institute of General Medical Sciences, which partially funded the work.
The discovery that human lincRNAs appear to function much like their zebrafish counterparts in embryonic development suggests that the framework will prove valuable in bringing new insights on the roles played by lincRNAs in mammalian organisms.”
The zebrafish is already a powerful tool for studying genetics. Whitehead Member Hazel Sive, who collaborated with Bartel and his lab members on the Cell paper, uses zebrafish to study brain development and genetic mutations linked to autism.
Says Sive, “The zebrafish is a fantastic, facile system for discovering the mechanisms by which genes work.”
“We humans share with zebrafish this subset of ancient, peculiar genes, and the functionality has been retained in them,” says Ulitsky. “We can perturb them in zebrafish and then replace them with the human ones and, at least in the lincRNAs we look at, the human ones function to restore proper development.”
“Because of this functional conservation of lincRNAs between zebrafish and humans, we’re introducing the zebrafish as a new vertebrate tool that could be used basically to uncover the functions of other lincRNAs,” says Shkumatava.
This work was supported by the National Institutes of Health’s (NIH’s) National Institute of General Medical Sciences (NIGMS), European Molecular Biology Organization (EMBO), Human Frontiers Science Program, and the National Science Foundation (NSF).
David Bartel is a Member at Whitehead Institute for Biomedical Research, where his laboratory is located and all his research is conducted. He is also a Howard Hughes Medical Institute Investigator and a professor of biology at Massachusetts Institute of Technology..
“Conserved function of lincRNAs in vertebrate embryonic development despite rapid sequence evolution”
Cell, December 23, 2011
Igor Ulitsky (1,2,3,5), Alena Shkumatava (1,2,3,5), Calvin H. Jan (1,2,3,4), Hazel Sive (1,3), David P. Bartel (1,2,3).
1. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, USA.
2. Howard Hughes Medical Institute.
3. Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
4. Present address: Howard Hughes Medical Institute and Department of Cellular and Molecular Pharmacology, UCSF, Genentech Hall S472C, 600 16th St, San Francisco, California 94143, USA.
5. These authors contributed equally to this work.
Whitehead Institute for Biomedical Research is a nonprofit, independent research and educational institution. Wholly independent in its governance, finances and research programs, Whitehead shares a close affiliation with Massachusetts Institute of Technology through its faculty, who hold joint MIT appointments.
Original article: http://www.wi.mit.edu/news/archives/2011/db_1222.html