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Six3 protein orchestrates a vital step in the formation of the embryonic forebrain
Researchers at St. Jude Children’s Research Hospital have discovered a critical, early step in the growing vertebrate embryo that is required for the proper development of a major part of what is often called the most complex structure in the universe—the human brain.
That vital step is orchestrated by the product of a single gene called Six3, which guides the formation of the embryonic part of the brain called the forebrain. The forebrain is destined to contain, among other structures, the eyes, olfactory center and cerebrum.
St. Jude scientists showed that the Six3 gene ensures proper development of the forebrain by halting the activity of another gene, called Wnt1, which had previously been shown to control the development of more posterior parts of the brain.
The action of the Six3 protein in directly blocking the activity of the Wnt1 protein prevents abnormal extension of the posterior part of the embryonic brain into what is normally destined to be the forebrain. Once protected by Six3, the forebrain matures, giving rise to some of the higher centers that control a variety of critical functions such as thought, memory and the senses of sight and smell.
“We showed that Six3 is one of the key elements preventing Wnt1 from disrupting normal development of the forebrain,” said Oleg V. Lagutin, PhD, a post-doctoral fellow in the Department of Genetics at St. Jude. Lagutin, who works in the laboratory of Guillermo Oliver, Ph.D., an associate member in the department, is the lead author of a report on this work, which appears in the Feb. 1, 2003 issue of the journal Genes & Development.
The St. Jude researchers showed that in mutant mice lacking both copies of the gene for Six3 (Six3-/- mice), there was abnormal extension of the posterior brain into the anterior area of the brain, i.e., the part that would normally have developed into the forebrain. This malformation was caused by the abnormal expansion of Wnt1 activity into this area.
“This finding indicates that what was eventually to become the forebrain was instead being turned into an extension of the posterior part of the brain,” Oliver said.
Anthony Carter, a program director at the National Institute of General Medical Sciences (of the National Institutes of Health), which partly funded the study said, "The work of Dr. Oliver and colleagues is an important step forward in defining a critical regulatory pathway for normal brain development. It's a new piece of the developmental puzzle.”
In a follow-up study, the scientists studied the role of Six3 in mutant (“headless”) zebrafish. In these fish, similar to the Six3-/- mice, the anterior, or rostral part of the head is missing due to the abnormal extension of Wnt1 activity into this region. When the researchers injected genetic material (messenger RNA, or mRNA) for mouse Six3 into the mutant zebrafish embryos, these mutant embryos developed a normal forebrain.
“The finding that the mouse gene for Six3 works in the zebrafish is not surprising,” Oliver said. “The Six3 gene doesn’t appear to change from fish to mammals. Six3 is obviously a profoundly important gene whose role in forebrain formation has been conserved in the animal kingdom.”
Previous work by a variety of laboratories showed that the early development of both the anterior and posterior brain is controlled by a number of different signals that are highly conserved among most vertebrates, according to Oliver.
“We’ve also known for a while that inhibition of Wnt1 signaling is required for the normal development of different areas of the forebrain,” Oliver says. “The finding by our lab that Six3 is one of the proteins responsible for that inhibition in the forebrain now helps to solve some of the mysteries of how such a complex entity like the brain develops in the embryo.”
In the past, mutations in Six3 were shown to contribute to holoprosencephaly (HPE), a brain defect in which the forebrain fails to divide into hemispheres during development, notes Oliver.
While HPE occurs in up to 1 in 5,000-10,000 live births, the real incidence may be as high as 1 in 200-250 fetuses, many of which are lost through spontaneous abortion, Oliver said.
Other researchers who contributed to this work include Changqi C. Zhu, Helen R. C. Russell and Peter J. McKinnon (Department of Genetics, St. Jude); Daisuke Kobayashi and Kenji Shimamura (University of Tokyo, Japan); and Jacek Topczewski and Lilianna Solnica-Krezel (Vanderbilt University, Nashville, TN).
Major funding for this work was provided by the National Institutes of Health, ALSAC and the Pew Scholars Program in Biomedical Sciences.
St. Jude Children’s Research Hospital
St. Jude Children’s Research Hospital, in Memphis, Tennessee, was founded by the late entertainer Danny Thomas. The hospital is an internationally recognized biomedical research center dedicated to finding cures for catastrophic diseases of childhood. The hospital’s work is supported through funds raised by ALSAC. ALSAC covers all costs not covered by insurance for medical treatment rendered at St. Jude Children's Research Hospital. Families without insurance are never asked to pay.