Title: The Disintegrin/Metalloproteinase ADAM10 Is Essential for the Establishment of the Brain Cortex
Authors: Jorissen, Ellen
Prox, Johannes
Bernreuther, Christian
Weber, Silvio
Schwanbeck, Ralf
Serneels, Lutgarde
Snellinx, An
Craessaerts, Kathleen
Thathiah, Amantha
Tesseur, Ina
Bartsch, Udo
Weskamp, Gisela
Blobel, Carl P
Glatzel, Markus
De Strooper, Bart ×
Saftig, Paul #
Issue Date: 7-Apr-2010
Publisher: The Society for Neuroscience
Series Title: Journal of Neuroscience vol:30 issue:14 pages:4833-4844
Abstract: The metalloproteinase and major amyloid precursor protein (APP) alpha-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 alpha-secretase-mediated processing of APP was largely reduced in these neurons, demonstrating that ADAM10 represents the most important APP alpha-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.
ISSN: 0270-6474
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for the Research of Neurodegenerative Diseases
× corresponding author
# (joint) last author

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