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Jorissen, Ellen; Prox, Johannes; Bernreuther, Christian; Weber, Silvio; Schwanbeck, Ralf; Serneels, Lutgarde; Snellinx, An; Craessaerts, Katleen; Thathiah, Amantha; Tesseur, Ina; Bartsch, Udo; Weskamp, Gisela; Blobel, Carl P.; Glatzel, Markus; De Strooper, Bart; Saftig, Paul

The Disintegrin/Metalloproteinase ADAM10 Is Essential for the Establishment of the Brain Cortex

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  • Media type: E-Article
  • Title: The Disintegrin/Metalloproteinase ADAM10 Is Essential for the Establishment of the Brain Cortex
  • Contributor: Jorissen, Ellen; Prox, Johannes; Bernreuther, Christian; Weber, Silvio; Schwanbeck, Ralf; Serneels, Lutgarde; Snellinx, An; Craessaerts, Katleen; Thathiah, Amantha; Tesseur, Ina; Bartsch, Udo; Weskamp, Gisela; Blobel, Carl P.; Glatzel, Markus; De Strooper, Bart; Saftig, Paul
  • imprint: Society for Neuroscience, 2010
  • Published in: The Journal of Neuroscience
  • Language: English
  • DOI: 10.1523/jneurosci.5221-09.2010
  • ISSN: 0270-6474; 1529-2401
  • Origination:
  • Footnote:
  • Description: <jats:p>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.<jats:italic>Adam10</jats:italic><jats:sup>−/−</jats:sup>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<jats:italic>Adam10</jats:italic>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<jats:italic>Adam10</jats:italic>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<jats:italic>Adam10</jats:italic>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.</jats:p>
  • Access State: Open Access