ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

Abstract

Neural precursor cells (NPCs) are activated in central nervous system injury. However, despite being multipotential, their progeny differentiates into astrocytes rather than neurons in situ. We have investigated the role of epidermal growth factor receptor (EGFR) in the generation of non-neurogenic conditions. Cultured mouse subventricular zone NPCs exposed to differentiating conditions for 4 days generated approximately 50% astrocytes and 30% neuroblasts. Inhibition of EGFR with 4-(3-chloroanilino)-6,7-dimethoxyquinazoline significantly increased the number of neuroblasts and decreased that of astrocytes. The same effects were observed upon treatment with the metalloprotease inhibitor galardin, N-[(2R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl]-L-tryptophan methylamide (GM 6001), which prevented endogenous transforming growth factor-a (TGF-a) release. These results suggested that metalloprotease-dependent EGFRligand shedding maintained EGFR activation and favored gliogenesis over neurogenesis. Using a disintegrin and metalloprotease 17 (ADAM-17) small interference RNAs transfection of NPCs, ADAM-17 was identified as the metalloprotease involved in cell differentiation in these cultures. In vivo experiments revealed a significant upregulation of ADAM-17 mRNA and de novo expression of ADAM-17 protein in areas of cortical injury in adult mice. Local NPCs, identified by nestin staining, expressed high levels of ADAM-17, as well as TGF-a and EGFR, the three molecules necessary to prevent neurogenesis and promote glial differentiation in vitro. Chronic local infusions of GM6001 resulted in a notable increase in the number of neuroblasts around the lesion. These results indicate that, in vivo, the activation of a metalloprotease, most probably ADAM-17, initiates EGFR-ligand shedding and EGFR activation in an autocrine manner, preventing the generation of new neurons from NPCs. Inhibition of ADAM-17, the limiting step in this sequence, may contribute to the generation of neurogenic niches in areas of brain damage.

Doxycycline increases neurogenesis and reduces microglia in the adult hippocampus

“…MMPs are soluble or membrane-bound proteases capable of degrading cell-surface receptors and extracellular matrix proteins, which play a role in tissue remodeling and receptor activation. MMPs are involved in several aspects of neurogenesis: MMP-17 prevents neurogenesis by shedding the ligand for, and activating EGFR (Epidermal growth factor receptor) and its inhibition results in increased neurogenesis (Romero-Grimaldi et al, 2011). MMP-3 and MMP-9 promote the differentiation and migration of neural progenitors (Barkho et al, 2008).…”

Developmental control of cortico-cerebral astrogenesis

“…In fact, both ligands are expressed in the neuronogenic cortical primordium (the former throughout it, the latter confined to its lateral border) (Assimacopoulos et al, 2003), but only Tgfa (and no Egf at all) is detectable in postnatal periventricular precursors (Romero-Grimaldi et al, 2011). Consistently with this prediction, mice expressing reduced Tgfa levels have a decreased number of astrocytes (Weickert and Blum, 1995).…”

“…In fact, Adam17 knock-down impairs astrogenesis and its expression levels go up in damaged brain regions undergoing astrogliosis. That, conversely, does not apply to Adam10 (Romero-Grimaldi et al, 2011).…”

“…Remarkably, the activity of A disintegrin and metallopeptidase domain (Adam) "sheddases" is required to make Egf/Tgfa ligands available in the extracellular space (Blobel, 2005), so enabling astrogenesis. Both Adam10 and Adam17 are co-expressed in the VZ of the mid-neuronogenic cortical primordium (Diez-Roux et al, 2011) as well as in periventricular precursors of postnatal cortex (Romero-Grimaldi et al, 2011). However only Adam17 seems implicated in astrogenesis promotion.…”

Nestin: Neural Stem/Progenitor Cell Marker in Brain Tumors

“…Many lines of evidence have shown nestin-positive brain cells to be neural stem/progenitor cells; therefore, a great deal of research has involved the use of nestin to detect neural stem cells [35][36][37]. Children, but not adult humans, exhibit nestin-positive cells in the subventricular zone of the third ventricle [6], and the human embryonic midbrain stem cell line NGC-407 showed degradation of nestin after induction of differentiation [38].…”