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Several neurological and neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia, have been found to be associated with mutations in transcription factor 4 (TCF4), a gene important in brain development
To explore this question, the researchers focused on Pitt-Hopkins syndrome, a type of ASD caused specifically by mutations in TCF4
Existing mouse models of Pitt-Hopkins syndrome cannot accurately mimic the neurological characteristics of patients, so the UC San Diego team created a model for human research
Preliminary observations of brain organoids revealed substantial structural and functional differences between samples with mutations in the TCF4 gene and controls
"Even without a microscope, you can tell which brain organoid is mutated," said senior study author Alysson R.
TCF4-mutated organoids were substantially smaller than normal organoids, and many of the cells were not actually neurons but neural progenitors
A series of experiments showed that mutations in TCF4 lead to dysregulation of the downstream SOX gene and the Wnt pathway, two important molecular signals that guide embryonic cells to proliferate, mature into neurons and migrate to their correct locations in the brain
Because of this dysregulation, neural precursor cells cannot multiply efficiently, resulting in fewer cortical neurons
This atypical cellular structure disrupts the flow of neural activity in the mutant brain organoids, which the authors say may lead to impaired cognitive and motor function
"We were surprised to find such major developmental problems at all these different scales, and it gave us an idea of what we could do to address them
The research team tested two different gene therapy strategies to restore functional genes in brain tissue
"The fact that we can correct this gene and the entire nervous system even rebuild itself at a functional level is surprising," Muotri said
Muotri noted that these genetic interventions occur during the prenatal stage of brain development, while in a clinical setting, children will be diagnosed and treated years later
"Any improvement in motor cognitive function and quality of life is worthwhile for these children and their loved ones," Muotri said