Molecular detector: Tiny hair-like projections called cilia (green) on the cell surface sense the external environment.
Image courtesy of Catarina Seabra lab
About five years ago, Catarina Seabra made a discovery that took her into uncharted scientific territory.
Siebra, then a graduate student in Michael Tarkovsky’s lab at Harvard University, discovered that disrupting the autism-associated gene MBD5 affected the expression of other genes in mouse brains and human neurons. did. Some of these genes are involved in the formation and function of primary cilia. Primary cilia are hair-like projections on the surface of cells that sense the external environment.
“Until that point, I had never heard of primary cilia in neurons, so this intrigued me,” says Seabra. She suspected that other researchers had linked cilia defects to conditions associated with autism, but the scientific literature provided sparse evidence, mainly in mice.
So Seebra, a group leader at the Center for Neuroscience and Cell Biology at the University of Coimbra in Portugal, set out to find connections between people. Autism or other neurodevelopmental conditions. And she plans to examine neurons and brain organoids made from those cells to see if those cilia exhibit any defects in structure or function.
Other neuroscientists are also working to understand the role of cilia during neurodevelopment. For example, last September, researchers working with tissue samples from mice discovered that cilia on the surface of neurons can form junctions, or synapses, with other neurons. activity. Beyond MBD5, other teams have linked several additional autism-related genes to small cellular antennae.
“Does that mean that the cilia are causal? [in autism]I don’t know,” says Helen Wilsey, an assistant professor of psychiatry at the University of California, San Francisco, who studies the relationship between autism-related genes and frog cilia. “But I think there’s definitely something going on with the cilia.”
aResearchers have yet to find a direct connection, but some tangential investigations link cilia to autism.
For example, features of autism may be part of a cilia-related disorder, or ciliopathy. Social difficulties and repetitive behaviors occur in up to 77% of people with Bardet-Biedl syndrome, a rare ciliary disease that causes kidney problems and vision loss, and up to 40% of people with Joubert syndrome. Malformed cerebellum and movement disorders.
Cilia deficiency is also associated with many other neurodevelopmental conditions, such as schizophrenia, tuberous sclerosis, and fragile X syndrome. Also, many genes associated with autism have interesting links to cilia. For example, reducing their expression can reduce the number of cilia on cells. Mice with mutations in the autism-related section of chromosome 16 show altered expression patterns of ciliary genes and abnormally short cilia in certain brain regions.
Rainbow Connection: Mouse hippocampal cilia can form junctions with other neurons.
The problem is that researchers “know almost nothing about primary cilia in neurodevelopmental conditions other than cilia,” says He Young Lee, assistant professor of cellular and integrative physiology at the University of Texas Health Science Center in San Antonio. said.
In a 2020 study, Lee’s team found that mice lacking FMR1, a gene mutated in people with fragile X syndrome, had fewer cilia in the dentate gyrus, a part of the hippocampus that contains neural progenitor cells. I showed that. Because cilia play an important role in cell division, fewer or defective cilia can affect brain development, Lee says.
But pinpointing the exact mechanisms involved is difficult, says Thomas Theil, reader in Developmental Biology at the University of Edinburgh, Scotland. “All possible processes in the development of the nervous system are controlled by cilia.”
T.Some altered processes are more likely than others to contribute to neurodevelopmental conditions, as not everyone with a defective ciliary gene is autistic.
During development of the cerebral cortex (the outer layer of the brain involved in higher cognitive functions), cilia are involved in several key events, including neuronal migration and axonal pathfinding, where neurons extend their projections to precise target areas. form the
And as part of the September discovery of synaptic connections between axons and cilia of neighboring neurons, researchers show that cilia are also involved in neurotransmission, transmitting signals between cells. I was. When axons release the neurotransmitter serotonin to ciliary receptors, a signaling cascade is triggered that opens a coiled complex of DNA and proteins in the nucleus of neurons, allowing proteins that turn genes on and off to access the DNA. You will be able to
“I was so excited when I found the cilia. […] Shusheng Shu, a senior scientist in David Clapham’s lab at the Janelia Research Campus in Ashburn, Virginia, and an investigator on the study, says.
Axon-ciliary synapses exist in mice as early as postnatal day 7, says Sheu. This timing means that cilia defects that affect neurotransmission during postnatal development may also contribute to several neurodevelopmental conditions.
“Ciliaries were already known to be important, but they are becoming increasingly important,” commented Kerstin Hasenpusch-Theil, a postdoctoral researcher in Theil’s lab, of the findings.
aSome investigators have focused on the possibility that cilia are functionally linked to neurodevelopment, while others suspect that these structures may be linked to autism-related genes. Note that there is
Willsey and her colleagues have previously shown that two genes associated with autism, DYRK1A and KATNAL2, are required for ciliogenesis and brain development in frogs. The gene localizes to and likely regulates the molecular components that form the ciliary scaffold.
Willsey plans to investigate whether other autism-related genes also localize to the cilia scaffold and how cilia are affected by silencing these genes. In addition, she is working on frogs that have cilia larger than mammalian cells.
If she and others can show that many different autism-related genes cluster in cilia defects, it would be ‘strong evidence’ of a causal link between cilia and autism. .
In Portugal, Seabra and her team recently discovered structural alterations in neuronal cilia from children with mutations in MBD5. MBD5 is the same autism-associated gene that started her research. Understanding the molecular mechanisms behind such cilia differences could suggest new therapeutic approaches, she says.
In the future, Seabra hopes to study these long-overlooked structures in neurons derived from people with idiopathic autism or autism without a genetic cause. But we’re mostly looking at neurons and synapses,” she says. “I want to put cilia on the autism map.”
Citing this article: https://doi.org/10.53053/CMZZ2213
