Novel Assay Provides Researchers a Key Tool to Study Nervous System Development

CAMBRIDGE, Mass. — For the first time, scientists at the Whitehead Institute for Biomedical Research have isolated embryonic tissue from zebrafish and successfully grown the tissue in culture. This assay will offer scientists a long-sought and powerful research tool, allowing them to study early development in ways that are not possible with other model organisms like frogs, mice, or chicks. Using this culture, the scientists also found that the formation of the zebrafish nervous system occurs in a similar fashion to higher vertebrates. The study is reported in the June issue of the journal Development and was led by Dr. Hazel Sive.

Scientists consider zebrafish an important model for studying development because its genes undergo many mutations during this process. However, until now, researchers had not been able to isolate tissue from zebrafish embryos because the embryos are tiny&emdash;about one fifth the size of a poppy seed. Dr. Sive and her coworkers mastered this difficult task using sensitive microdissection techniques. The in vitro assays they have developed will provide valuable insights into vertebrate development and shed light on the developmental mechanisms that go awry in some common human birth defects, including microencephaly and spina bifida.

"Many of the genetic mechanisms involved in development are conserved among species. For this reason, what we learn about key pathways required for the development of a zebrafish will also be important for understanding the development of a human being," says Dr. Sive.

She and many other scientists have long sought to understand how a vertebrate embryo decides to make a nervous system and where the various regions of that nervous system will form. These decisions are made early in development, within the first three weeks after conception in humans&emdash;before most women know they are pregnant&emdash;and have profound consequences for later sensory and motor function and behavioral responses. Finding the genes that participate in this process also could lead to new strategies for repairing defects in the human nervous system due to injury or disease.

Scientists study early developmental events using various animal models, including frogs, chicken, mice, and zebrafish. Each model has its own advantages and disadvantages. Frogs, for example, offer an excellent system for developmental studies, but they are not well-suited for genetic analysis because they have a two-year generation time. Zebrafish, by contrast, have a two-month generation time allowing their development to be studied by gene mutation. One drawback of the zebrafish has been a lack of understanding of when and how the body plan is first set up. Part of the reason for this problem has been inability to analyse early development using the "classical" embryological techniques of isolation and culture of tissues. Zebrafish embryos are very small, making it difficult for researchers' efforts to isolate specific tissues and grow them in culture — until now.

The in vitro assays developed in Dr. Sive's laboratory will enhance the role of the zebrafish model and provide valuable insights into the molecular signals that control one of the earliest stages of vertebrate development, establishment of the head-to-tail orientation. Dr. Sive's studies focus primarily on pattern formation in the ectoderm, the embryonic tissue that gives rise to the brain and the spinal cord, non-neural glands, and the epidermis of the skin.



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