Control of adult neurogenesis by programmed cell death in the mammalian brain

Abstract

The presence of neural stem cells (NSCs) and the production of new neurons in the adult brain have received great attention from scientists and the public because of implications to brain plasticity and their potential use for treating currently incurable brain diseases. Adult neurogenesis is controlled at multiple levels, including proliferation, differentiation, migration, and programmed cell death (PCD). Among these, PCD is the last and most prominent process for regulating the final number of mature neurons integrated into neural circuits. PCD can be classified into apoptosis, necrosis, and autophagic cell death and emerging evidence suggests that all three may be important modes of cell death in neural stem/progenitor cells. However, the molecular mechanisms that regulate PCD and thereby impact the intricate balance between self-renewal, proliferation, and differentiation during adult neurogenesis are not well understood. In this comprehensive review, we focus on the extent, mechanism, and biological significance of PCD for the control of adult neurogenesis in the mammalian brain. The role of intrinsic and extrinsic factors in the regulation of PCD at the molecular and systems levels is also discussed. Adult neurogenesis is a dynamic process, and the signals for differentiation, proliferation, and death of neural progenitor/stem cells are closely interrelated. A better understanding of how adult neurogenesis is influenced by PCD will help lead to important insights relevant to brain health and diseases.

Death begets a new beginning

“…As in development, neurogenesis in these regions is accompanied by substantial cell death . Phagocytosis, by microglia as well as non‐microglial cells, has been experimentally linked with adult neurogenesis (Figure D).…”

“…112,113 As in development, neurogenesis in these regions is accompanied by substantial cell death. [114][115][116] Mice lacking other phagocytic receptors, such as TAM TKO mice, also displayed a defect in neurogenesis in the DG, with around 60% fewer BrdU + DCX + neuronal precursors/neuroblasts than in WT DG. 118 However, crossing of Axl −/− Mertk −/− to Interleukin-6 −/− mice restored BrdU + DCX + neuronal precursors/neuroblasts numbers closer to those of the WT, indicating that a constant low level of inflammation in the TAM KO mice may be what is harmful to neuronal differentiation, rather than an impaired phagocytic process.…”

Adult neurogenesis – accent on subgranular and subventricular zone in mammals

“…Budući da hipotalamična adultna neurogeneza može biti stimulirana različitim vanjskim čimbenicima kao što je vrsta prehrane, hormoni i dr., ukazuje na potencijalna lječidbena otkrića za mnoge metaboličke poremećaje. No još uvijek se smatra da NSCs u tom području, kao i u ostalim gore navedenima, posjeduju nizak stupanj spontane proliferacije u fiziološkim uvjetima u odnosu na onaj u SVZ-u i SGZ-u, te uglavnom bivaju potaknute u bolesti 13,14 . Iz tog razloga, a ujedno i zbog važnosti reguliranja tjelesne homeostaze koja zaslužuje posebnu obradu, u daljnjem tekstu osvrt će biti samo na primarne dvije germinativne regije (SVZ i SGZ).…”

Medulloblastoma initiation and spread: Where neurodevelopment, microenvironment and cancer cross pathways

“…One of the last and most prominent processes of neurogenesis is programmed cell death, which regulates the final number of mature neurons into neural circuits. This cellular pruning, which is an integral mode of cell death in neural stem/progenitor cells, can be classified into apoptosis, necrosis, and autophagic cell death (Ryu et al, ). Furthermore, intrinsic and extrinsic factors are key in the regulation of program cell death of cerebellar neural progenitor cells (Dekkers et al, ).…”