summary: A brain organoid study shows how a genetic mutation linked to Pitt-Hopkins syndrome, a profound form of autism, impairs neural development. Using gene-editing techniques, the researchers retrieved the function of the TCF4 gene and effectively restored neural structure and function.
Source: ucsd
In a study published in nature communication Scientists at the University of California San Diego School of Medicine used human brain organoids to reveal how a genetic mutation closely linked to a profound form of autism disrupts neural development.
Neural structure and function were effectively rescued by using gene therapy tools to correct the function of the gene.
Several neurological and neuropsychiatric diseases, including autism spectrum disorder (ASD) and schizophrenia, have been linked to mutations in transcription factor 4. tcf4), an essential gene in brain development.
Transcription factors control when other genes are turned on or off, so their presence, or lack thereof, can exert a domino effect in the developing embryo. Yet, little is known about what happens to the human brain when tcf4 is mutated.
To explore this question, the researchers focused on Pitt-Hopkins syndrome, an ASD caused by mutations in particular tcf4, Children with the genetic condition have profound cognitive and motor disabilities and are usually non-verbal.
Existing mouse models of Pitt-Hopkins syndrome fail to accurately mimic the neural characteristics of patients, so the UC San Diego team created a human research model of the disorder instead. Using stem cell technology, they transformed the patients’ skin cells into stem cells, which were later developed into three-dimensional brain organoids, or “mini-brains.”
Early observations of brain organoids revealed a slew of structural and functional differences between them tcf4 Mutated samples and their controls.
Senior study author Alison R., a professor at UC San Diego School of Medicine, director of the UC San Diego Stem Cell Program, and member. “Even without a microscope, you can tell which part of the brain the mutation occurred in,” Muotri said. Sanford Consortium for Regenerative Medicine.
tcf4 The mutated organoids were much smaller than normal organoids, and many of the cells were not actually neurons, but neural progenitors. These simple cells are meant to multiply and then mature into specialized brain cells, but in the mutated organoids, some part of this process went awry.
A series of experiments showed that tcf4 Mutations caused downstream dysregulation socks The gene and the Wnt pathway, two important molecular signals that guide embryonic cells to multiply, mature into neurons, and move to the correct location in the brain.
Because of this pathology, neural progenitors did not multiply efficiently and thus produced fewer cortical neurons. Cells that matured into neurons were less excitable than normal and often clustered together rather than organizing themselves into finely-tuned neural circuits.
This abnormal cellular architecture disrupted the flow of neural activity in the mutated brain organoids, which the authors said would contribute to impaired cognitive and motor function down the line.
First author Fabio Pepes, PhD, associate professor at the University of Campinas and visiting scholar at UC, said, “We were surprised to see such major developmental issues at all these different scales, and it surprised us that we could address them.” What can I do to do that?” San Diego School of Medicine, who jointly supervised the work with Muotri. Pepps has a relative with Pitt-Hopkins syndrome, which prompted him to study tcf4,
Microscopy images reveal significant differences in size and structure between brain organs obtained from a patient with Pitt–Hopkins syndrome (right) and a control (left). credit: UCSD
The team tested two different gene therapy strategies to fix functional genes in brain tissue. both methods effectively increased tcf4 level, and in doing so, corrected the Pitt-Hopkins syndrome phenotype at the molecular, cellular and electrophysiological scales.
“The fact that we can fix this one gene and the entire nervous system rewires itself, even on a functional level, is surprising,” Muotri said.
Muotri notes that these genetic interventions occurred at a prenatal stage of brain development, whereas in a clinical setting, children would receive diagnosis and treatment a few years later. Thus, clinical trials should first confirm whether subsequent interventions are still safe and effective.
The team is currently adapting their recently licensed gene therapy tool in preparation for such a trial, in which spinal injection of a genetic vector would fine-tune TCF4 function in the brain.
“For these children and their loved ones, any improvement in motor-cognitive function and quality of life will be well worth the effort,” Muotri said.
Audrey Davido, president of the Pitt Hopkins Research Foundation, said, “The really outstanding thing about this work is that these researchers are going beyond the lab and working hard to make these findings translatable to the clinic. ” “It is much more than a stellar academic paper; it is the perfect measure of what science can achieve in hopes of changing human lives for the better.”
Co-authors include: Janena S. at UC San Diego. De Souza, Ryan A. Szato, Erin LaMontagne, Simoni H. At the University of Campinas, Antonio P. Camargo, Vinicius MA Carvalho, Jose R. Teixeira, Thiago S. Nakahara, Carolina N. Santo, Barbara MP Araujo and Paulo ENF Velho.
About this genetics and ASD research news
Author: nicole malinrich
Source: ucsd
contact: Nicole Mlinerich – UCSD
image: Image credits to UCSD
Basic Research: open access.
Alison R. “Transcription factor 4 loss-of-function is associated with a reduction in progenitor proliferation and cortical neuron content” by Muotri et al. nature communication
Summary
see all
Transcription factor 4 loss-of-function is associated with a reduction in progenitor proliferation and cortical neuron content
transcription factor 4 (tcf4) Associated with autism, schizophrenia and other neuropsychiatric disorders. However, how pathological tcf4 Mutations affecting human nervous tissue are poorly understood.
Here, we derived neural progenitor cells, neurons, and brain organoids from skin fibroblasts derived from children with Pitt–Hopkins syndrome, which contain clinically relevant mutations. tcf4,
We show that neural progenitors that bear these mutations have reduced proliferation and impaired ability to differentiate into neurons.
We identify a mechanism through which tcf4 Loss-of-function decreases Wnt signaling and then decreases expression of socks gene, resulting in reduced progenitor proliferation in vitro.
Furthermore, we show reduced cortical neuron content and impaired electrical activity in patient-derived organoids, phenotypes that were rescued after correction tcf4 expression or by pharmacological modulation of Wnt signalling.
This work delineates the pathological mechanism harboring nerve cells. tcf4 Mutations and genetic disorders involving this gene provide a potential target for therapeutic strategies.