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

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.

Pubmed ID: 20371803

Authors

  • Jorissen E
  • Prox J
  • Bernreuther C
  • Weber S
  • Schwanbeck R
  • Serneels L
  • Snellinx A
  • Craessaerts K
  • Thathiah A
  • Tesseur I
  • Bartsch U
  • Weskamp G
  • Blobel CP
  • Glatzel M
  • De Strooper B
  • Saftig P

Journal

The Journal of neuroscience : the official journal of the Society for Neuroscience

Publication Data

April 7, 2010

Associated Grants

  • Agency: NEI NIH HHS, Id: EY015719
  • Agency: NIGMS NIH HHS, Id: GM64750
  • Agency: NEI NIH HHS, Id: R01 EY015719
  • Agency: NEI NIH HHS, Id: R01 EY015719-06
  • Agency: NIGMS NIH HHS, Id: R01 GM064750
  • Agency: NIGMS NIH HHS, Id: R01 GM064750-09
  • Agency: NIGMS NIH HHS, Id: R01 GM064750-09S1

Mesh Terms

  • ADAM Proteins
  • Amyloid Precursor Protein Secretases
  • Amyloid beta-Protein Precursor
  • Animals
  • Animals, Newborn
  • Cell Differentiation
  • Cell Proliferation
  • Cells, Cultured
  • Cerebral Cortex
  • Female
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Neurogenesis
  • Pregnancy
  • Receptors, Notch