A new approach has enabled researchers to prevent cleft palate in mice genetically engineered to develop that birth defect. The scientists used a technique that they crafted to identify the short period when a particular gene is turned on as a fetus develops. The tool may give clues to the cause of cleft palate and other birth defects in people.
The process that creates a complex, multicellular animal out of a single fertilized egg cell typically relies on the coordinated activity of thousands of genes. Individual genes must create proteins precisely when they’re needed, and the genes often turn on and off more than once during development.
Scientists have a variety of tools to investigate the roles that each gene plays throughout this process. However, most of those tools eliminate a gene or permanently shut off its activity early in development. Scientists can’t then tell at what time the gene’s activity becomes important.
“That’s a level of precision that we haven’t been able to achieve,” says Michael Longaker, a pediatric craniofacial surgeon at Stanford University School of Medicine in Palo Alto, Calif.
To gain more insight into the timing of gene activity, Longaker and his colleagues focused on a mouse gene called glycogen synthase kinase-3b (GSK-3b). Previous studies had linked this gene to palate and breastbone development.
The researchers engineered mice with a chemical tag on GSK-3b that made the protein produced by this gene degrade rapidly. Like mice engineered to lack the gene, they developed cleft palates and malformed breastbones, and they died at birth.
However, the chemical tag was constructed so that a drug called rapamycin would prevent the GSK-3b protein from degrading. When the researchers gave rapamycin throughout pregnancy to female mice carrying fetuses with the chemical tag, the babies were born healthy and didn’t show the typical birth defects.
To specify when fetuses need the GSK-3b protein to develop normally, Longaker’s team gave rapamycin during a variety of 2-day stretches to groups of female mice carrying fetuses with the chemical tag. The researchers report in the March 1 Nature, that the GSK-3b protein participates in palate development and breastbone formation at different times. Mice whose mothers were treated with the drug between 13.5 to 15 days after gestation were spared cleft palates, but normal breastbone development required treatment between days 15.5 to 17.
“This really nails down the windows when the gene is critical,” Longaker says.
Randall Peterson, a developmental biologist at Massachusetts General Hospital in Boston, calls the new technique “pretty exciting.” He says, “What you really want is the ability to test when specific genes are required and what roles they play at different times during development. This technique allows you to do that with decent temporal control.”
A better grasp of which genes are important at which times during development, Peterson adds, may eventually enable physicians to treat cleft palate and other birth defects before a baby is born.