Lead and Mercury Disrupt Neuronal Stem Cells: Mechanism Identified

Mark Noble, Ph.D.
Department of Biomedical Genetics, University of Rochester Medical Center
R01ES012708

Groundbreaking research from Mark Noble at the University of Rochester concludes that low levels of diverse environmental agents, namely lead, methylmercury, and paraquat, disrupt the normal functioning of progenitor cells within the central nervous system.

Noble and his colleagues found a previously unknown mechanism by which these agents cause the effects. The agents make the cells more oxidized, which causes the activation of an enzyme known as Fyn kinase, which in turn activates another enzyme called c-Cbl. C-Cbl modifies and degrades protein receptors necessary for cell division and survival. When the receptors are degraded, their downstream signaling pathways are repressed and the cells fail divide and develop properly.

The work was conducted in cell cultures of glial progenitors, advanced-stage stem cells important for the growth and development and normal functioning of the central nervous system. The cells proved to be exquisitely sensitive to minute levels of the toxicants. The pathway they activate is a normal cellular regulatory pathway; however, according to the authors,“they are just activating it inappropriately.”

The discovery of a molecular target that is shared by a variety of compounds may represent a new tool for rapidly screening compounds to determine their potential neurotoxicity. It may also provide insights into how to protect cells from the signaling disruption once exposure has occurred.

Citation: Li Z, Dong T, Proschel C, Noble M. Chemically Diverse Toxicants Converge on Fyn and c-Cbl to Disrupt Precursor Cell Function. PLoS Biol. 2007 Feb;5(2):e35.