干细胞研究有助确定精神分裂症的源头

New University at Buffalo¹ research demonstrates how defects in an important neurological pathway in early development may be responsible for the onset² of schizophrenia later in life. The UB findings, published in Schizophrenia Research, test the hypothesis in a new mouse model of schizophrenia that demonstrates how gestational（妊娠期的） brain changes cause behavioral problems later in life -- just like the human disease.

 

The genomic pathway, called the Integrative Nuclear FGFR 1 Signaling (INFS), is a central intersection³ point for multiple pathways of as many as 160 different genes⁵ believed to be involved in the disorder⁶.

 

"We believe this is the first model that explains schizophrenia（精神分裂症） from genes to development to brain structure and finally to behavior," says lead author Michal Stachowiak, PhD, professor in the Department of Pathology and Anatomical Sciences in the UB School of Medicine and Biomedical Sciences. He also is director of the Stem Cell Engraftment & In Vivo Analysis Facility at the Western New York Stem Cell Culture and Analysis Center at UB.

 

A key challenge with the disease is that patients with schizophrenia exhibit mutations in different genes, he says.

 

"How is it possible to have 100 patients with schizophrenia and each one has a different genetic⁸ mutation⁷ that causes the disorder?" asks Stachowiak. "It's possible because INFS integrates diverse neurological signals that control the development of embryonic⁹ stem cell and neural¹⁰ progenitor¹¹ cells, and links pathways involving schizophrenia-linked genes.

 

"INFS functions like the conductor of an orchestra," explains Stachowiak. "It doesn't matter which musician is playing the wrong note, it brings down the conductor and the whole orchestra. With INFS, we propose that when there is an alteration¹² or mutation in a single schizophrenia-linked gene⁴, the INFS system that controls development of the whole brain becomes untuned. That's how schizophrenia develops."

 

Using embryonic stem cells, Stachowiak and colleagues at UB and other institutions found that some of the genes implicated¹³ in schizophrenia bind¹⁴ the FGFR1 (fibroblast growth factor receptor) protein, which in turn, has a cascading¹⁵ effect on the entire INFS.

 

"We believe that FGFR1 is the conductor that physically¹⁶ interacts with all genes that affect schizophrenia," he says. "We think that schizophrenia occurs when there is a malfunction¹⁷ in the transition from stem cell to neuron, particularly with dopamine neurons."

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