Lost Neuron: At day 8, immature mouse neurons lacking ZFP462 (bottom row) have high levels of FOXA2 protein (purple) and promote non-neuronal cell development. FOXA2 is almost absent from the controls (top row) at this stage.
Just weeks after the sperm and egg combine, the human embryo forms into a three-layered horseshoe, each responsible for producing its own specialized cells.
It is in the ectoderm layer, the birthplace of the nervous system, that the autism-associated gene ZNF462 plays a key role, according to a new mouse study. Without that block, some cells destined for the brain end up with irrelevant functions, delaying neuronal development.
“The normal time course of differentiation is confusing,” said lead investigator Oliver Bell, assistant professor of biochemistry and molecular medicine at the University of Southern California, Los Angeles.
Bell came to ZNF462 in 2017 while searching for new genes involved in chromatin regulation. Bell’s interest was in chromatin function, but many epistatic genes associated with autism and neurodevelopmental problems are involved in the process.
People with only one functioning copy of ZNF462 have Weiss-Kruska syndrome, a rare condition characterized by characteristic facial features, developmental delay, and sometimes autism. In 2017, Paul Kruszka, then a clinical geneticist at the National Human Genome Institute in Bethesda, Maryland, discovered the condition after he discovered a mutation in ZNF462 while screening the exomes of people with developmental delay. was first explained. At the time, little was known about this gene. In 2019, he had only 24 people known to have the condition.
“This is great,” said Krushka, now chief medical officer of genetic testing company GeneDx, of Bell’s paper. “He goes deep into the biology of ‘What does this gene do?'”
T.o To examine the function of the gene, Bell and his team disrupted the function of one or both copies of the ZNF462 equivalent mouse ZFP462 in mouse embryonic stem cells. When stem cells replicate, they spread out more than wild-type cells and cluster into tight domes. The self-indulgent distribution suggests abnormal cell differentiation early in development, says Bell.
Genes that fine-tune cells to become muscle, connective tissue, gut, and other organs (normally activated only in the two other layers of the embryo, mesoderm and ectoderm) are deficient in ZFP462. It was found by researchers to be upregulated in stem cells that have
The team also found that embryoid bodies and neural progenitor cells derived from edited stem cells were smaller than those from wild-type. Also, mesoderm and endoderm gene expression is not reduced in mutant progenitor cells as in controls.
Cells destined to become neurons may remain in a more plastic state longer, says Bell. “They are either disorganized cells simply because they have not matured properly, or they are essentially lost and contributed to another lineage.”
The survey results are nature cell biology in January.
T.The downstream effects of the extra unlucky cells are unknown and are an important target for future research, says Sophia Lizaraga, professor of biology and medicine at Brown University in Providence, Rhode Island. . He wasn’t involved in this research.
“I think that’s the great thing about this piece,” Lizaraga says. “It raises a lot of questions in terms of what to do next.”
Other genes that alter heterochromatin (a dense form of chromatin that suppresses unwanted gene expression) are involved in neurodevelopment and have been linked to autism. For example, ADNP appears to repress endoderm genes and regulate genes that help determine cell fate.
“There is a theme that this kind of machine is being used in neurodevelopment,” says Bell.
Given that it’s activated so early in development, it’s unclear how and what therapeutics could target this mechanism, says Bell. They plan to study ZNF462 mutations in cortical organoids, which they say may reveal therapeutic opportunities.
But Krushka is more optimistic. Clinicians don’t know which of his ZNF462 mutations lead to which outcome, so it’s difficult to advise families who do sequencing, he says.
“He’s answering two questions: What is a meaningful subspecies and what does that subspecies do?” Krushka says. “It’s a logical next step towards some kind of therapy.”
Citing this article: https://doi.org/10.53053/ONUL6683