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

Abstract

The metalloproteinase and major amyloid precursor protein (APP) ␣-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 ␣-secretasemediated processing of APP was largely reduced in these neurons, demonstrating that ADAM10 represents the most important APP ␣-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.

5-HT4 Receptors Constitutively Promote the Non-Amyloidogenic Pathway of APP Cleavage and Interact with ADAM10

“…30 This assumption was confirmed by RNAi-mediated silencing of ADAM10 and by using conditional ADAM10 knockout mice. 24,32 These findings were extended by the present study, which revealed association of the 5-HT 4 R with ADAM10. The ability of 5-HT 4 R to physically interact with mature ADAM10 was not shared by other GPCRs known to stimulate sAPPα secretion upon stimulation by their respective agonists.…”

ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A

“…Genetic ablation of ADAMs in the nervous system causes a 1 day delay in the loss of responsiveness to Sema3A both in vitro and in vivo. The complete physiological significance of this delay remains unresolved, since Nestin-Cre ADAM10 cKOs die at birth 58 . Thus, full assessment of the delay's implications on the correct wiring of proprioceptive fibres awaits the generation of more specific conditional knockouts.…”

SFRPs act as negative modulators of ADAM10 to regulate retinal neurogenesis

“…Furthermore, recent studies have convincingly demonstrated that at least in the CNS Notch, APP and N-cadherin are ADAM10 specific substrates 22,43 . In line with these findings, we have demonstrated that the proteolytic processing of these three substrates, as well as that of L1-CAM, is altered in Sfrp1/2 null mice.…”

“…Supporting this interpretation, we showed that pharmacological inhibition of ADAM10 can rescue the enhanced cell proliferation of Sfrp1 -/-;Sfrp2 -/-neural retina. Furthermore, conditional inactivation of Adam10 in neural progenitor cells causes a depletion of early progenitors and a reduction of α-secretase-mediated processing of APP 22 , a phenotype opposite to that observed in Sfrp1/2 null retinas or in the cortex of Sfrp1 -/-embryos (I. Crespo, P. Bovolenta and P.…”