Switch that controls neuronal migration in developing brain identified

WASHINGTON - Researchers at St. Jude Children’s Research Hospital have identified a crucial step in brain development, which offers insight into the origins of epilepsy, mental retardation and possibly brain tumour metastasis.

They have identified key components of a signaling pathway that controls the departure of neurons from the brain niche where they form and allows these cells to start migrating to their final destination.

Defects in this system affect the architecture of the brain and are associated with epilepsy, mental retardation and perhaps malignant brain tumours.

“Neurons are born in germinal zones in the brain, and the places they occupy in the mature brain are sometimes quite a distance away. The cells have to physically move to get to that final destination,” said David Solecki.

“If the process is compromised, the result is devastating disruption of brain circuitry that specifically targets children,” he added.

The team also identified the adhesion molecule that functions as the cells’ exit ticket.

Solecki and his colleagues showed that high levels of Siah E3 ubiquitin ligase block neuronal departure by tagging a critical part of the cell’s migration machinery for degradation through a process known as ubiquitination. Siah’s target is Pard3A, which is part of the PAR complex.

The researchers showed that only when neuronal production of Siah falls and Pard3A rises will the cells move out of the germinal zone. The change prompts the cells to alter their migratory path and move toward the location where they will incorporate into the brain’s circuitry. The findings mark the first instance of PAR complex activity being regulated by an ubiquitin-targeting protein like Siah.

Investigators went on to show that Siah-Pard3A regulates neuronal migration via the adhesion molecule JAM-C, which is short for junctional adhesion molecule C.

Researchers demonstrated that silencing JAM-C production in the neurons or preventing JAM-C binding to Pard3A blocked neuronal migration out of the germinal zone.

“Until now, cell adhesion was difficult to detect and the techniques involved were laborious. With this approach, it is almost as if the cells are telling us what they are doing. It was very exciting for me to look at a dish of living neurons and see adhesion occur for the first time,” said Solecki.

The study appears November 25 in the journal Science. (ANI)