Results of a study using three-dimensional (3-D) “minibrains” generated in a laboratory shed new light on the link between mutant disrupted-in-schizophrenia 1 (DISC1) genes and schizophrenia.
Dr Tracy Young-Pearse
Using cultured human induced pluripotent stem cells, researchers created 3-D cerebral organoids to study the neurodevelopmental consequences of mutant DISC. They used the gene editing tool CRISPR-Cas9 to disrupt DISC1 to model the mutation seen in studies of families with schizophrenia.
The cerebral organoids with DISC1 disruption are morphologically distinct from wild-type organoids, report Tracy Young-Pearse, PhD, and colleagues from the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital, Boston, Massachusetts.
A few weeks after formation, wild-type cerebral organoids show well-defined rosette and ventriclelike structures that contain mitotic neural progenitor cells. In contrast, cerebral organoids from DISC1-disrupted cells display an increased number of small, disorganized rosette structures.
These observations highlight “the promise of using cerebral organoids for disease modeling, allowing the discovery of morphological phenotypes that cannot be as easily studied with monolayer cultures,” the researchers write.
The study was published online April 12 in Translational Psychiatry.
The DISC1-mutant minibrains also show increased signaling in the WNT pathway, which is known to be important for patterning organs and to be disrupted in patients with bipolar disorder, say the researchers.
“Interestingly,” they note, adding an inhibitor of the WNT pathway to growing DISC1-mutant cerebral organoids “rescues” them; instead of having structural differences, they come resemble wild-type cerebral organoids. This suggests that the WNT pathway may be responsible for the observed structural disruption in the DISC1 mutants and raises the possibility that the WNT pathway could be a target for future therapies.
Novel Technology
“In order to develop new therapies for mental illness, we want to be able to better understand what happens in the brain — the molecular pathways and cellular processes — that leads to mental illness,” Young-Pearse told Medscape Medical News. “We can see the human brain through imaging, but until recently, it was very difficult to obtain living human brain cells for study, ” she added.
“Human induced pluripotent stem cell technology coupled to new technologies for directing these cells to become brain cells now allows us to generate these living human brain cells in a dish that we can carefully study. Through a better understanding of disease processes in the human brain, we hope to identify new targets for drug development, ” said Young-Pearse.
Reached for comment, Juergen Knoblich, PhD, of the Institute of Molecular Biotechnology, Vienna, Austria, said, “Using cerebral organoids to model neuropsychiatric diseases is in principle very interesting [and] DISC1 mutant organoids have been generated before.”
Young-Pearse said that going forward, there are multiple avenues to pursue.
“This study focused on one particular gene linked to mental illness. We and many others are studying additional genetic influencers of disease and are hoping to identify common pathways that would be good targets for therapeutic development. In addition, many of us in the field are working to improve these ‘minibrain-in-a-dish’ models to more and more closely recapitulate the complexity of the human brain.”
The study was supported by funding from the Sackler Scholar Programme in Psychobiology, a Young Investigator Award from the Brain and Behavior Research Foundation, and the National Institute of Mental Health. The authors have disclosed no relevant financial relationships.
Transl Psychiatry. Published online April 12, 2018. Full text
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