The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex.
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The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex. / 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; Bart, De Strooper; Saftig, Paul.
in: J NEUROSCI, Jahrgang 30, Nr. 14, 14, 2010, S. 4833-4844.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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T1 - The disintegrin/metalloproteinase ADAM10 is essential for the establishment of the brain cortex.
AU - Jorissen, Ellen
AU - Prox, Johannes
AU - Bernreuther, Christian
AU - Weber, Silvio
AU - Schwanbeck, Ralf
AU - Serneels, Lutgarde
AU - Snellinx, An
AU - Craessaerts, Katleen
AU - Thathiah, Amantha
AU - Tesseur, Ina
AU - Bartsch, Udo
AU - Weskamp, Gisela
AU - Blobel, Carl P
AU - Glatzel, Markus
AU - Bart, De Strooper
AU - Saftig, Paul
PY - 2010
Y1 - 2010
N2 - 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.
AB - 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.
M3 - SCORING: Zeitschriftenaufsatz
VL - 30
SP - 4833
EP - 4844
JO - J NEUROSCI
JF - J NEUROSCI
SN - 0270-6474
IS - 14
M1 - 14
ER -
