RT Journal Article
SR Electronic
T1 The Disintegrin/Metalloproteinase ADAM10 Is Essential for the Establishment of the Brain Cortex
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4833
OP 4844
DO 10.1523/JNEUROSCI.5221-09.2010
VO 30
IS 14
A1 Ellen Jorissen
A1 Johannes Prox
A1 Christian Bernreuther
A1 Silvio Weber
A1 Ralf Schwanbeck
A1 Lutgarde Serneels
A1 An Snellinx
A1 Katleen Craessaerts
A1 Amantha Thathiah
A1 Ina Tesseur
A1 Udo Bartsch
A1 Gisela Weskamp
A1 Carl P. Blobel
A1 Markus Glatzel
A1 Bart De Strooper
A1 Paul Saftig
YR 2010
UL http://www.jneurosci.org/content/30/14/4833.abstract
AB 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.