such as "Introduction", "Conclusion"..etc
Scientists have identified a gene family that plays a key role in one of
the earliest stages of development in which an embryo distinguishes its
left side from the right and determines how organs should be positioned
within the body. The finding in mice likely will lead to a better
understanding of how certain birth defects occur in humans.
The study is published in the January 24, 2010, advance online issue
of the journal Nature Cell Biology.
"Having clear knowledge of embryonic development and how certain
developmental processes can go awry is imperative for understanding the
causes of the various types of human birth defects, which may eventually
help us devise ways to correct those defects," said Anthony
Wynshaw-Boris, MD, PhD, chief of medical genetics at UCSF Children's
Hospital and a co-senior author of the study.
In the current study, the research team built upon previous work that
uncovered the mechanism within the embryo responsible for specifying
its left and right sides -- a process called left-right symmetry
breaking. That research, conducted by geneticist Hiroshi Hamada, MD,
PhD, and colleagues at Japan's Osaka University, showed how tail-like
projections known as cilia located on the surface of cells in an
embryonic region called the node generate a leftward flow of fluid
outside the embryo, which, in turn, lets the embryo know which side is
In this earlier work, Hamada's group discovered that the cilia are
able to produce a leftward flow of fluid because they are located toward
the back of the node cells and are tilted toward the embryo's tail end.
This unique placement, coupled with the cilia's clockwise circular
beating motion, results in the leftward flow and, subsequently, the
embryo's left-right symmetry breaking. According to the researchers, if
this directional flow is not established, organisms can develop with
their internal organs on the wrong side of the body, decreasing chances
"Knowing that the cilia's placement on the node is intricately
involved with this key stage of embryonic development, we decided to
take our work a step further to see whether certain genes might
determine how cilia retain this tilted position," said Hamada, who is
also a co-senior author of the current study.
Hamada and Wynshaw-Boris decided to look at whether a specific gene
family, called the "Dishevelled" gene family, might be directing the
cilia's migration to the back side of the node cells. Having researched
this gene family for many years, the Wynshaw-Boris lab developed mouse
models with each of the three Dishevelled genes "turned off" to study
their individual functions. In doing so, they found that the Dishevelled
genes activate a genetic pathway, called the planar cell polarity
pathway, which helps determine positional information in cells and
"We focused on the Dishevelled gene family because from our previous
work, we knew that these genes were involved in the development of hair
cells within the inner ear of the embryo, and that the cilia-like
structures at the edge of the hair cells behave in a similar fashion as
those on the node of the embryo. That similarity made us take a closer
look at how this gene family was acting on correct placement of the
nodal cilia at this very early stage of development," Wynshaw-Boris
Masakazu Hashimoto, a graduate student in the Hamada lab and the
first author of the study, monitored the movement of cilia in live mouse
embryos using a high-speed camera attached to a microscope and observed
that the cilia's position actually changed as development proceeded. In
the very earliest stages -- before left-right symmetry breaking
occurred -- cilia were located in the center of the node cells; then, as
development progressed, the cilia gradually moved to the back side of
The researchers compared cilia in normal mouse embryos to those in
embryos with mutated versions of all three Dishevelled genes. They found
that the cilia in the mutant embryos were misplaced on the node cells
and therefore unable to produce a leftward flow of fluid.
"This discovery provides exciting information about how we are built
the way we are at the most basic of levels: that is, how do we
differentiate our left side from our right? Ultimately this determines
how the heart ends up on the left side of the body and the liver on the
right side, for example," Wynshaw-Boris added.
Additional co-authors include Kyosuke Shinohara, Shingo Ikeuchi,
Satoko Yoshiba, and Chikara Meno, all of Osaka University's
Developmental Genetics Group; Jianbo Wang of the University of
California, San Diego, Department of Pediatrics and Medicine; Shigenori
Nonaka of Japan's National Institute for Basic Biology; Shinji Takada of
the Okazaki Institute for Integrative Biosciences; and Kohei Hatta of
the University of Hyogo Graduate School of Life Science.
The research was supported by a grant from Core Research for
Evolutional Science and Technology of the Japan Science and Technology
Corporation and a grant-in-aid from the Ministry of Education, Culture,
Sports, Science, and Technology of Japan, as well as grants from the
National Institutes of Health and March of Dimes.
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