Nestin Regulates Neurogenesis in Mice Through Notch Signaling From Astrocytes to Neural Stem Cells

Abstract

The intermediate filament (nanofilament) protein nestin is a marker of neural stem cells, but its role in neurogenesis, including adult neurogenesis, remains unclear. Here, we investigated the role of nestin in neurogenesis in adult nestin-deficient (Nes–/–) mice. We found that the proliferation of Nes–/– neural stem cells was not altered, but neurogenesis in the hippocampal dentate gyrus of Nes–/– mice was increased. Surprisingly, the proneurogenic effect of nestin deficiency was mediated by its function in the astrocyte niche. Through its role in Notch signaling from astrocytes to neural stem cells, nestin negatively regulates neuronal differentiation and survival; however, its expression in neural stem cells is not required for normal neurogenesis. In behavioral studies, nestin deficiency in mice did not affect associative learning but was associated with impaired long-term memory.

Nestin affects fusion pore dynamics in mouse astrocytes

“…We previously demonstrated the role of nestin in the regulation of neurogenesis via Notch signalling from astrocytes to neural stem cells . Notch signalling from Nes −/− astrocytes to neural stem cells was decreased, probably by the inability of Nes −/− astrocytes to sustain Notch activation of neural stem cells over time .…”

“…We previously demonstrated the role of nestin in the regulation of neurogenesis via Notch signalling from astrocytes to neural stem cells . Notch signalling from Nes −/− astrocytes to neural stem cells was decreased, probably by the inability of Nes −/− astrocytes to sustain Notch activation of neural stem cells over time . The trafficking of vesicles containing the Notch ligand Jagged‐1 was altered in Nes −/− astrocytes: the number of internalized Jagged‐1 + vesicles was lower and the fraction of internalized Jagged‐1 that co‐localized with Rab5a, an early endosomal marker, was higher in Nes −/− compared to wt astrocytes, indicating that nestin plays a role in regulating the segregation of Jagged‐1 into distinct vesicular compartments .…”

“…Notch signalling from Nes −/− astrocytes to neural stem cells was decreased, probably by the inability of Nes −/− astrocytes to sustain Notch activation of neural stem cells over time . The trafficking of vesicles containing the Notch ligand Jagged‐1 was altered in Nes −/− astrocytes: the number of internalized Jagged‐1 + vesicles was lower and the fraction of internalized Jagged‐1 that co‐localized with Rab5a, an early endosomal marker, was higher in Nes −/− compared to wt astrocytes, indicating that nestin plays a role in regulating the segregation of Jagged‐1 into distinct vesicular compartments . In this study, we further addressed the role of nestin in astrocyte vesicle dynamics by examining whether nestin affects the vesicle fusion pore, vesicle trafficking and Ca 2+ signalling.…”

Intermediate filaments in developing neurons: Beyond structure

“…From both of these studies nestin appeared not essential for neural development, but was important for myogenesis and neuromuscular junction (NMJ) formation, and behaviorally resulted in poor performance in the rotarod test due to decreased muscle coordination. Surprisingly, adult neurogenesis was found to be impaired in the viable nestin KO strain by an unexpected non‐cell autonomous mechanism where nestin‐expressing astrocytes regulate Notch signaling in progenitors to maintain stemness (Wilhelmsson et al, ). In addition, some behavioral defects were described in the same paper, in particular with respect to long‐term memory in an object recognition test (Wilhelmsson et al, ).…”

“…The underlying mechanism is by altering the distribution of fate‐inducing molecules to affect results of cell divisions—be it differentiation, continued proliferation, or cell death. Depletion of nestin in neural stem cells and myoblasts has been shown to induce premature differentiation (Pallari et al, ; Wilhelmsson et al, ), but the NPC pathway is not thought to be via cdk5 regulation, but via affecting numb segregation. Again, confusion exists because the effects are not the same in all systems.…”