CAMBRIDGE, Mass. — MIT Picower Institute for Learning and Memory researchers digging deeply into one of the developing brain’s signaling pathways uncovered new details on how a key gene is implicated in psychiatric diseases such as schizophrenia and bipolar disease. The knowledge could lead to better drug targets for these disorders.
“Despite efforts to better identify disease pathology, understanding the causes of these devastating diseases remains elusive,” said co-author Karuna Singh, Picower Institute postdoctoral fellow. Working with Li-Huei Tsai, Picower Institute professor and director, Singh and colleagues investigated a gene called Dixdc1 that has been pegged as a risk factor for schizophrenia and other mood disorders that affect millions of Americans.
Psychiatric disorders run in families. Researchers are seeking to identify the genes involved and how they confer increased risk for developing these diseases.
The first risk gene discovered was named DISC1 (disrupted-in-schizophrenia-1.) DISC1 helps regulate the structural formation of the brain by acting as a traffic cop, guiding newly formed neurons to their proper destinations and forming connections among developing neurons. Previously, the Picower researchers found that DISC1 helps expand the pool of neural stem cells.
The current study found that Dixdc1, which stands for Dix domain containing-1, is a key modulator of DISC1 in the developing brain and shuttles DISC1 to different molecular signaling pathways during key stages of brain development.
The Picower researchers report that together, DISC1 and Dixdc1 activate a signaling cascade that generates neurons. Later, when the newly born neurons are migrating to their appropriate destinations, Dixdc1 re-targets DISC1 to interact with another signaling pathway that regulates the structure of neurons while they migrate.
Dixdc1 is involved in a signaling pathway tied to human psychiatric disease and the mechanisms underlying psychotropic drugs, said Tsai, a Howard Hughes Medical Institute investigator. “Future studies that determine whether other candidate psychiatric risk genes also interact with this signaling pathway will help us understand the pathways disrupted in psychiatric disease.”
To determine whether Dixdc1 regulates neural progenitor proliferation, the researchers knocked down the expression of Dixdc1 in mice. They then over-expressed DISC1, which restored normal function even after Dixdc1 was knocked out.
Given that Dixdc1 has a similar function to DISC1 and helps regulate it, further studies will help determine whether there are distinct mutations in Dixdc1 in particular families that confer risk for psychiatric disease.
Source: “Dixdc1 is a critical regulator of DISC1 and embryonic cortical development,” Karun K. Singh, Xuecai Ge, Yingwei Mao, Laurel Drane, Konstantinos Meletis, Benjamin A. Samuels, Li-Huei Tsai. Neuron, 15 July 2010.
Funding: National Institutes of Health
contact: Jen Hirsch – MIT News Office
written by: Deborah Halber, MIT’s Picower Institute for Learning and Memory