Paternal control in neuronal stem cells

Researchers have shown for the first time how the paternally imprinted factor Zac1 controls the development of neuronal stem cells

During the development of each human being, a kind of “genetic tug war” takes place in the mother’s womb. Whereas paternal genes are interested in exploiting a large share of the maternal resources, maternal genes try to shield the mother’s organism from excessive strain. Researchers at the Max Planck Institute of Psychiatry have made an important step in explaining how this parental gene conflict can affect brain development. By studying neuronal stem cells in culture and in mice, they have shown for the first time how the paternal factor Zac1 critically inhibits or promotes the differentiation of neuronal stem cells in astroglial cells.

The highly complex brain arises from an initially small cluster of precursor cells. Millions of stem cells have to systematically develop into nerve or glial cells according to a genetically specified schedule. Glial cells are so-called supporting cells. Among these, astroglial cells serve as a supporting structure for neurons and additionally nourish them.

“With our current study, we have shown for the first time in detail how Zac1 is activated in differentiating neuronal stem cells and induces Socs3 during the development of astroglial cells,” Udo Schmidt-Edelkraut, first author of the study, explains. Although the effect of imprinted genes onto the development of the brain has been generally known for a long time, the underlying cellular mechanism remained largely unknown.

The Zac1 gene is only active when expressed from the paternal chromosome of the DNA and encodes the corresponding Zac1 protein, which controls the differentiation of astroglial cells via an indirect control mechanism. For this purpose, it binds to several regulatory DNA regions and controls the formation of another protein – Socs3. Socs3, in turn, has the task to inhibit the transition of neuronal stem cells into supporting cells which is necessary for future brain development. In the event of reduced Zac1 expression, this genetic “brake” is lost and astroglial cells begin to proliferate in an unstrained manner, which can lead to malformation of neuronal networks.

“Our results have shown a possible cellular mechanism for the different influence of parental genomes on later brain diseases,” Udo Schmidt-Edelkraut says.

As with all higher organisms, in human beings as well, the paternal and maternal halves of the double set of chromosomes are not identical but differ in function. Typically, both copies of the 25,000 human genes are active. In the case of 100 to 200 genes, however, only one parental allele is active. Depending on the parental origin of the silenced allele, it is called to be paternally or maternally imprinted. The underlying mechanisms of imprinting involve among others DNA methylation, which results in lasting on/off switches in gene activity.

“Imprinted genes play an important role in embryonic development and physiology,” Udo Schmidt-Edelkraut explains. Thus, loss of imprinting might frequently cause severe malfunctions of metabolism or brain functions, e.g., early childhood diabetes or the Angelman Syndrome characterized by cognitive impairments, hyperactivity and attention deficits.

For their study, the researchers investigated stem cell cultures of mice and humans and compared them to stem cells in mice brain. Based on their data, they concluded that Socs3 was a direct target gene of Zac1 both in humans and in mice. Socs 3 had been previously isolated as a Zac1 target gene via a genome-wide expression profiling in neuronal stem cells.

MG