The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex

E Jorissen, J Prox, C Bernreuther, S Weber… - Journal of …, 2010 - Soc Neuroscience
E Jorissen, J Prox, C Bernreuther, S Weber, R Schwanbeck, L Serneels, A Snellinx…
Journal of Neuroscience, 2010Soc Neuroscience
The metalloproteinase and major amyloid precursor protein (APP) α-secretase candidate
ADAM10 is responsible for the shedding of proteins important for brain development, such
as cadherins, ephrins, and Notch receptors. Adam10−/− mice die at embryonic day 9.5, due
to major defects in development of somites and vasculogenesis. To investigate the function
of ADAM10 in brain, we generated Adam10 conditional knock-out (cKO) mice using a Nestin-
Cre promotor, limiting ADAM10 inactivation to neural progenitor cells (NPCs) and NPC …
The metalloproteinase and major amyloid precursor protein (APP) α-secretase candidate ADAM10 is responsible for the shedding of proteins important for brain development, such as cadherins, ephrins, and Notch receptors. Adam10 −/− mice die at embryonic day 9.5, due to major defects in development of somites and vasculogenesis. To investigate the function of ADAM10 in brain, we generated Adam10 conditional knock-out (cKO) mice using a Nestin-Cre promotor, limiting ADAM10 inactivation to neural progenitor cells (NPCs) and NPC-derived neurons and glial cells. The cKO mice die perinatally with a disrupted neocortex and a severely reduced ganglionic eminence, due to precocious neuronal differentiation resulting in an early depletion of progenitor cells. Premature neuronal differentiation is associated with aberrant neuronal migration and a disorganized laminar architecture in the neocortex. Neurospheres derived from Adam10 cKO mice have a disrupted sphere organization and segregated more neurons at the expense of astrocytes. We found that Notch-1 processing was affected, leading to downregulation of several Notch-regulated genes in Adam10 cKO brains, in accordance with the central role of ADAM10 in this signaling pathway and explaining the neurogenic phenotype. Finally, we found that α-secretase-mediated processing of APP was largely reduced in these neurons, demonstrating that ADAM10 represents the most important APP α-secretase in brain. Our study reveals that ADAM10 plays a central role in the developing brain by controlling mainly Notch-dependent pathways but likely also by reducing surface shedding of other neuronal membrane proteins including APP.
Soc Neuroscience