EMBL: A protein required for the normal development of the brain

Research lead

Researchers from the Mouse Biology Unit of the European Molecular Biology Laboratory (EMBL) in Italy have discovered a protein required for the normal development of the brain that could be applied to treat disorders including epilepsy, schizophrenia and lissencephaly – a form of mental retardation.

The researchers found that mice lacking the protein called n-cofilin show symptoms of lissencephaly brought about by faulty development of the cerebral cortex, the surface layer of the brain.

“We genetically engineered mice that lack n-cofilin and they show the same anatomical defects and symptoms as patients suffering from lissencephaly,” says Walter Witke, whose team carried out the research. “Their brains miss several cortical layers because neurons do not migrate normally during development.”

The ability of neurons to migrate is largely brought about by the dynamic properties of their skeleton. The skeleton of a cell consists of constantly growing and shrinking filaments that function like strings and struts to give the cell shape and stability. N-cofilin interacts with one kind of filament, actin, and helps to disassemble it. This impairs the cell’s ability to move and thus blocks migration of neurons during cortical development.

N-cofilin also controls the fate of neural stem cells, which are involved in development of the cortex. In its absence more stem cells stop to self-renew and instead start differentiating. This imbalance depletes the pool of neuronal progenitors, so that fewer cells can be made to build a complete and functional cortex.

The study provides the first proof that proteins affecting actin filament dynamics are involved in neuronal migration disorders.

“This might have implications for humans, too,” says Gian Carlo Bellenchi from Witke’s lab. “Like many other cytoskeletal proteins n-cofilin is conserved between mice and humans and it is likely to play a similar role in the development of the human cortex.”

This makes the gene encoding n-cofilin an interesting candidate that might be mutated in neuronal disorders such as lissencephaly and other forms of mental retardation.

The studies also identified n-cofilin as a potential target molecule that might interfere with stem cell function in diseases where stem cell division has derailed.”