Genes known to cause birth defects may also lead to mental illness

Genetic mutations known to cause major birth defects in developing embryos are now being implicated in another significant health condition: mental illness.

Researchers from the University of California, San Francisco examined mutations of the gene Dact1 in mice, which disrupts the encoding of the Dact1 protein – and leads to the disruption of cell signaling pathways during embryonic development.  When scientists manipulated the gene in mice after they had developed normally, they found that it caused subtle disruptions in the brain, potentially contributing to psychiatric disorders such as schizophrenia, autism and bipolar disorder.

“(The gene is) present in the forebrain cortex, part of the brain just behind your forehead that’s involved in executive decision making, as well as deeper parts of the brain involved in fear and anxiety,” lead researcher Dr. Benjamin Cheyette, in UCSF’s Nina Ireland Laboratory of Developmental Neurobiology. “It’s generally present in all brain cells at different stages of development.”

The Dact1 protein is involved in a group of biological pathways known as Wnt signaling.  Comprised of proteins responsible for passing signals between the outside and inside of cells, the Wnt signaling pathways help to coordinate many essential biological processes in humans and animals such as fruit flies and mice.

Conversely, mutations along these pathways have been shown to lead to various cancers and birth defects.  The term Wnt is derived from two words – “wingless” and “integration” – which represent two major health conditions caused by Wnt signaling mutations in animals.

“This pathway was first described in fruit flies; if there’s a mutation in one of the pathways (during development), it causes a fly to have no wings,” Cheyette explained.  “…At the same time, the same pathway was discovered in mice by people studying cancer, and …they discovered it’s the target of a virus in mice that causes breast cancer – or the integration site of this virus. That’s when it was thought to be important in embryonic development and cancer.”

Previous research has also hinted at possible behavioral problems resulting from Wnt signaling mutations, ultimately prompting Cheyette to focus on the Dact1 gene – which he had discovered when he was a postdoctoral fellow studying the Wnt pathways.

In order to better understand how the Dact1 mutation affects mice post-development, Cheyette and his team used a technique called conditional mutation, which allowed them to turn the Dact1 gene on and off in the brains of genetically engineered mice during different stages of development. First, the gene was turned “on” and functioned normally during the mice’s embryonic development, allowing them to grow without birth defects. Then, once the mice were grown, the scientists turned the gene off and studied the effects of this protein disruption.

“What if we let the gene do its thing during development, but then eliminate it in the brain once they are grown?” Cheyette said.  “That’s where we’re finding there are interesting effects on the shape of neurons and connections between brain cells.”

Cheyette’s team observed that when the gene was switched off, the mice’s brain cells appeared relatively normal. However, they had significantly fewer synapses and their structural shapes were somewhat off.  According to Cheyette, these changes in the brain cells closely resembled those of individuals with psychiatric illness.

The team’s discovery could have major implications for future treatments for psychiatric illness, since regulating the Dact1 gene may help improve brain circuitry.  However, the researchers noted that more research needs to be done on the Dact1 gene in humans to better understand why those with birth defects do not always have psychiatric illness – and vice versa.

“One answer is that it could have to do with individual genetic variations within the human population,” Cheyette said.  “You may have other differences in genetic makeup that make you more or less susceptible to psychiatric illness.  These could help determine if you’re born with birth defects or look quite normal and then go on to have mental problems.”

Ultimately, Cheyette said his findings provide hope for the development of new drugs to help combat psychiatric illnesses, like depression and anxiety.  He said that this study provides a brand new mechanism of action for getting to the heart of the disorder, whereas current psychiatric medications only address the symptoms, not the illness’s cause.

“With this Wnt signaling pathway, hopefully the pharmaceutical companies take notice and say we should look at drugs that affect this pathway and see if they have effects on behavior in treating depression or anxiety,” Cheyette said. “We have had a lot of psychiatric drugs, but they are pretty much slight variations from Prozac or previously existing antipsychotics.  There are not a lot of pharmaceutical agents that are really completely new in terms of acting on different mechanisms.”

The research was published online in the journal PLOS ONE.