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.
Jorissen
Ellen
E
Center for Human Genetics, Katholieke Universiteit Leuven, Vlaams Instituut voor Biotechnologie (VIB), 3000 Leuven, Belgium.
Prox
Johannes
J
Bernreuther
Christian
C
Weber
Silvio
S
Schwanbeck
Ralf
R
Serneels
Lutgarde
L
Snellinx
An
A
Craessaerts
Katleen
K
Thathiah
Amantha
A
Tesseur
Ina
I
Bartsch
Udo
U
Weskamp
Gisela
G
Blobel
Carl P
CP
Glatzel
Markus
M
De Strooper
Bart
B
Saftig
Paul
P
D051722:ADAM Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D000072197:ADAM10 Protein; D053829:Amyloid Precursor Protein Secretases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology* / Q000201:enzymology* / Q000254:growth & development; D005260:Female; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055495:Neurogenesis / Q000235:genetics / Q000502:physiology; D011247:Pregnancy; D051880:Receptors, Notch / Q000096:biosynthesis / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; C078201:Aplp1 protein, mouse; D008565:Membrane Proteins; D051880:Receptors, Notch; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human