How much is currently known about what happens in the developing brain that puts people at risk of schizophrenia?
Over 25 years ago, it was proposed that schizophrenia is a mental disorder with a developmental origin, which has been supported by brain imaging and post-mortem studies.
For example, structural brain imaging studies have consistently shown a subtle, almost universal, decrease in grey matter, enlargement of ventricles, and focal alteration of white matter tracts. The exact cause that leads to these structural changes is still largely unknown.
How have previous studies identified genetic mutations that are more common in people with schizophrenia?
The genetic risks for schizophrenia are identified through linkage, association or genome-wide association studies (GWAS).
What schizophrenia-linked genetic variations have been discovered and which variation did your research study?
During the past two decades, many genetic variants in different forms (gene mutations, SNPs: single nucleotide polymorphism and CNVs: copy number variations) have been identified to be linked to schizophrenia.
In our study, we focused on one of these: CNVs at 15q11.2. In this case, patients are missing a small portion of their DNA on chromosome 15. The deleted region contains 4 genes.
Please can you tell us how you used skin cells from people with schizophrenia to study the impact of the missing part of 15q11.2?
We used a technology called induced pluripotent stem cell technology to transform dermal skin cells into cells with pluripotency (iPSCs) by reprogramming these cells with transcription factors.
These iPSCs can then be differentiated into cells with neural lineage, which maintain the same genetic composition as the donor individual.
Why do normal neural progenitors form orderly rings when grown in a dish and how did you find out which of the genes in the missing piece of the genome were responsible for those with the deletion not growing in this way?
Neural rosettes (orderly rings) are the developmental signature of neural progenitors in culture and are formed by radial arrangements of columnar cells, which mimic the organization of neuroepithelial cells in the neural tube during fetal development.
The maintenance of this ring structure requires actin cytoskeleton. Among the 4 genes affected by this 15q11.2 CNV, CYFIP1 had been previously shown to be linked to actin regulation.
Our study from multiple levels of analyses provides evidence to support CYFIP1 as a potential major contributing factor to biological processes implicated in the neurodevelopmental origins of these disorders.
What did your results reveal about the changes that occur in the developing brain of people with schizophrenia?
First, we have identified a novel phenotype in early neural progenitor stages using human iPSCs and confirmed these findings in vivo using animal models.
Second, as a functional consequence of CYFIP1 deficiency, neural progenitors and their neuronal progeny are aberrantly localized in the developing cortex in vivo, resulting in altered stratification of projection neurons and malformation of cortical layers.
As deficits in cortical patterning have been suggested in schizophrenia, our studies thus provide direct support for the developmental origin of schizophrenia.
What impact do you think this research will have?
First, using human iPSCs as a leading discovery tool, our study generated new insight into the underlying pathophysiology arising from genetic variation associated with risk for schizophrenia.
Second, we reveal a mechanistic link between the15q11.2 CNV, which has been implicated in risk for several psychiatric disorders, and key neural developmental processes that have also been implicated in several psychiatric disorders.
Third, our integrated mechanistic and human genetic study implicates, for the first time, WAVE signalling in schizophrenia-a new signalling pathway and target for future investigation and potential drug development.
What further research is needed to help increase our understanding of the causes of schizophrenia?
Further understanding of how this genetic risk might affect behaviour will shed light on the pathophysiology of schizophrenia and functional consequences of specific deficits in brain development.
Where can readers find more information?
About Professor Guo-li Ming
The research of Dr. Guo-li Ming’s laboratory centers on understanding the molecular mechanisms underlying neuronal development during embryonic stages and in the adult brain and underlying psychiatric mental disorders with neural developmental origin, with a particular focus on the signaling events involved in cell morphogenesis, cell migration, and axon/dendritic guidance.
She has been serving as a Steering committee member of Neuroscience Graduate Program, a member of the Office of Women in Science and Medicine advisory group of JHMI, a committee member of JHU ISCRO and a member of the Mentoring Program “Women in Neuroscience” of Society for Neuroscience.