La
Jolla, CA (8/6/98)- How do developing cells know which way to turn
as an organism grows? Salk Institute researchers have discovered a gene
that may explain this fundamental mystery.
Dr. Juan Carlos Izpisúa Belmonte and colleagues report that misexpression
of a gene called Pitx2 leads to alterations in the relative position
of organs and the direction of body rotation in the embryos of chicks,
the frog frog Xenopus. Mutations of this gene in mice were shown
to produce what are known as laterality defects.
Image: The left-hand image
shows a normal embryo of the frog Xenopus, with rightward looping heart
and anti-clockwise coiled gut. On the right, additional Pitx2 at the 4-cell
stage leads to leftward-looping heart and a clockwise gut.
A cascade of molecule signals helps steer the course of early
embryonic development in all vertebrates. Since many of these are only
expressed momentarily, the reserchers set their sites on finding the main
genetic 'switch' responsible for directing, propagating and maintaining
developmental symmetery.
"What we found is a fundamental discovery of a pivotal gene that controls
embryonic handedness in vertebrates. The results ultimately may help us
explain severe and debilitating human malformations associated with the
incorrect positioning of the viscera at birth in either normal babies or
in conjoined twins," said Dr. Belmonte.
The researchers had observed that the Pitx2 gene was expressed predominantly
on the left side of developing mouse, chick, frog and fish embryos. A left
or sinister-sided bias was also seen in developing organs, including the
heart, gut or liver. They studied a mutant mouse born with its organs in
a reversed position and found that the Pitx2 gene was expressed on the
right side of the mutant embryo that later gave rise to organs located
in the opposite side of their normal relatives.
"That was the first indication that this gene is linked to the establishment
of the left-right axis," said Dr. Belmonte.
They ten determined that injecting the gene along the right side of
embryonic chicks made the embryos attempt to organize themselves in reverse
of what would be expected normally. For example, while a heart normally
begins as a straight tube amd then loops to the right as it developes,
the heart tubes in the test animals curled in the opposite direction. Similar
reversals were seen during the formation of the gut and the body's rotation.
The researchers had knwon of the existence of several genes that
appeared to direct proper left-right orientations in a variety of vertebrates,
but were mystified when some of these genes appeared to turn off before
any visible asymmetry appeared. This prompted the search for the master
gene.
"With this one gene we were able to put an entire organ on the other
side," said Belmonte. "That's a major significance of this study. You don't
need thousands of genes to do this, just one gene that activates many genes
downstream."
The research could lead to an improved understanding of vertebrate development
and evolution, as well as the medical problems suffered by people with
congenital 'laterality defects'. For example, mutations in one copy of
the Pitx2 gene have been linked to a rare genetic disorder called Rieger
Syndrome that is characterized by, among other things, irregular-shaped
eyes leading to glaucoma, craniofacial deformities and cardiac anomalies.
The research appears in the August 6, 1998 issue of Nature.
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