by St. Jude Children’s Research Hospital

Research from the Zakharenko lab, St. Jude Department of Developmental Neurobiology published in Nature Communications revealed a gene deleted in 22q11.2 deletion syndrome results in malformed regions of the cerebellum, but the defect is a result of a local skull deformity. Pictured: first author on the paper Tae-Yeon Eom, PhD. Credit: St. Jude Children’s Research Hospital

The chromosomal disorder 22q11.2 deletion syndrome (22q) has emerged as one of the strongest risks for schizophrenia. Scientists at St. Jude Children’s Research Hospital identified malformed regions of the cerebellum in laboratory models and patients with 22q and found that these malformations were caused by improper skull formation. Further, the researchers linked the skull malformation to the loss of one gene: Tbx1.

The research shows that neurological disorders can stem from sources beyond the nervous system, such as improper skull development. The findings were published today in Nature Communications.

Schizophrenia develops in about 30% of people with 22q. In addition, the large region of the genome that is affected in 22q is conserved among many animals, making 22q ideal for studying the genetic basis of schizophrenia in laboratory models. This provided the corresponding author, Stanislav Zakharenko, MD, Ph.D., St. Jude Department of Developmental Neurobiology, a launchpad to study the syndrome and explore its link to neurological development.

Gene removal blocks skull pocket from forming

Previous work from Zakharenko found that the deletion of only one 22q gene, Dgcr8, disrupts the flow of auditory information from a lower brain region called the thalamus to the auditory cortex, where sounds are interpreted. This region of the brain is also associated with auditory hallucinations, which are a hallmark symptom of schizophrenia. The researchers called this breakdown in information flow “thalamocortical disruption.”

“Although thalamocortical disruption occurs late in development, which is consistent with the onset of schizophrenia symptoms, it stays and doesn’t go away. However, hallucinations are transient in nature—they come and go,” Zakharenko said. “It seemed that this was just one of the hits that triggered symptoms. The question is: What is the other hit?”

The researchers noticed a part of the brain, the cerebellum, malformed in 22q animal models, specifically, the cerebellum’s small lobules called the flocculus and paraflocculus. Most neurodevelopmental disorders arise from defects in genes that play a role in the brain, but the 22q gene the researchers linked to this malformation, Tbx1, was unexpected.

Paraflocculus/flocculus dysplasia in mouse models and human subjects with 22q11DS. Credit: Nature Communications (2024). DOI: 10.1038/s41467-024-54837-3

“What is interesting about Tbx1 is that it is not very well expressed in the brain, especially the adolescent or adult brain,” Zakharenko said. “Rather, it’s expressed in the surrounding tissues, namely bone, cartilage and vasculature tissues. It is very unlikely that Tbx1 directly affects the brain at all.”

Instead, removing Tbx1 has an indirect but significant effect on brain development. Bone formation relies on immature osteoblast cells correctly growing into mature osteocytes. Tbx1 removal disrupted this cycle, resulting in an underdeveloped pocket in the skull which normally houses the flocculus and paraflocculus.

For a neurological syndrome, the findings are strikingly unusual—with no pocket in the skull for these structures to develop, they appear substantially smaller than normal. The reduction of the flocculus and paraflocculus was validated through magnetic resonance imaging studies of dozens of patients with 22q and a comparative control group.

Misshapen skull removes cerebellum’s checks and balances

Zakharenko’s team studied the flocculus and paraflocculus’ role in the brain to better understand how their malformation could influence behavior. “We found that the neural circuits within the flocculus and paraflocculus are dysfunctional,” explained Zakharenko.

The regions also control a reflex that ensures stable vision during head movements and is crucial for face recognition. The researchers found that this reflex is impaired in 22q. This may be a valuable lead for schizophrenia research because patients with schizophrenia have a deficit in face recognition.

The paraflocculus is also connected to the auditory cortex. However, the details of such connectivity are unclear. Zakharenko hopes future research will more clearly reveal the links between 22q and schizophrenia. More specifically, he hopes that future research will illuminate how the paraflocculus affects the function of the auditory cortex and provide us with the second hit that leads to hallucinations.

“In my mind, it’s like a stepping stone. We hope to follow this chain of events from the malformed skull to the underdeveloped flocculus and paraflocculus to the auditory cortex dysfunction,” Zakharenko said. “This would be extraordinary because it all started with a bone.”

More information: Tae-Yeon Eom et al, Tbx1 haploinsufficiency leads to local skull deformity, paraflocculus and flocculus dysplasia, and motor-learning deficit in 22q11.2 deletion syndrome, Nature Communications (2024). DOI: 10.1038/s41467-024-54837-3

Journal information:Nature Communications

Provided by St. Jude Children’s Research Hospital

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