Involvement of Notch1 Signaling in Neurogenesis in the Subventricular Zone of Normal and Ischemic Rat Brain in Vivo

Abstract

The Notch1 signaling pathway is regarded as one of the main regulators of neural stem cell behavior during development, but its role in the adult brain is less well understood. We found that Notch1 was mainly expressed in doublecortin (DCX)-positive cells corresponding to newborn neurons, whereas the Notch1 ligand, Jagged1, was predominantly expressed in glial fibrillary acidic protein (GFAP)-positive astrocytic cells in the subventricular zone (SVZ) of the normal adult brain. These findings were confirmed by conditional depletion of DCX-positive cells in transgenic mice carrying herpes simplex virus thymidine kinase (HSV-TK) under the control of the DCX promoter. In addition, the activated form of Notch1 (Notch intracellular domain, NICD) and its downstream transcriptional targets, Hes1 and sonic hedgehog (Shh), were also expressed in SVZ cells. Increased activation of Notch1 signaling increased SVZ cell proliferation, whereas inhibiting Notch1 signaling resulted in a reduction of proliferating cells in the SVZ. Levels of NICD, Hes1, and Shh were increased in the SVZ at 4 and 24 h after focal cerebral ischemia. Finally, ischemia-induced cell proliferation in the SVZ was blocked by inhibition of the Notch1 signaling pathway, suggesting that Notch1 signaling may have a key role in normal adult and ischemia-induced neurogenesis.

Role of neural precursor cells in promoting repair following stroke

“…The interaction between the two cell types has been suggested to play a role in regulating the proliferation of NPCs in the SVZ [108] . In a rat MCAO model, a transient increase in the expression of Notch signalling molecules are seen up to 24 h post-ischemia [108] . In vitro administration of Notch ligands and inhibitors modulate NPC proliferation and differentiation in post-ischemic NPCs [107,109] .…”

“…In vitro administration of Notch ligands and inhibitors modulate NPC proliferation and differentiation in post-ischemic NPCs [107,109] . Intraventricular injection of Notch activators in vivo lead to increased cell proliferation in the SVZ for up to 24 h [108] , and has been shown to improve motor deficits in mice over a 45 d period [108,109] . Thus various signalling pathways contribute post-ischemia to the expansion of the NPC pool through the inhibition of apoptosis, change in the cell cycle kinetics, mode of cell division, and regulation of proliferation.…”

“…The transmembrane Notch receptor and its downstream targets are expressed on NPCs in the SVZ, while the Notch ligands -Jagged1 and Delta1 -are expressed by astrocytic GFAP + cells [107,108] . The interaction between the two cell types has been suggested to play a role in regulating the proliferation of NPCs in the SVZ [108] . In a rat MCAO model, a transient increase in the expression of Notch signalling molecules are seen up to 24 h post-ischemia [108] .…”

Notch signaling in the brain: In good and bad times

“…Neural stem cells of the SGZ and SVZ, which are quiescent under physiological conditions, have been shown to proliferate following injury (Kawai et al, 2005;Lugert et al, 2010), probably in an attempt to repair brain damage. Notch signaling, which is a known neurogenic factor (Gaiano and Fishell, 2002), has been shown to be central in this process, as demonstrated by genetic and chemical loss of function models (Kawai et al, 2005;Oya et al, 2009;Wang et al, 2009;Xin et al, 2006). Interestingly, this regenerative potential, in response to injury, is diminished with aging (Lugert et al, 2010).…”

“…In addition, Notch activation has been shown to be essential in neural stem cell proliferation in several hypoxia-ischemia rodent models (Androutsellis-Theotokis et al, 2006;Carlen et al, 2009;Chen et al, 2008a;Oya et al, 2009;Wang et al, 2009). Canonical Notch signaling is activated through a hypoxia-dependent mechanism (Johnson, 2011;Seidel et al, 2010), as well as through overexpression of the ligand (Androutsellis- Theotokis et al, 2006;Liu et al, 2011).…”