Zhang R, Engler A, and Taylor V.
Jun 15, 2017
Notch signaling is evolutionarily conserved from Drosophila to human. It plays critical roles in neural stem cell maintenance and neurogenesis in the embryonic brain as well as in the adult brain. Notch functions greatly depend on careful regulation and cross-talk with other regulatory mechanisms. Deregulation of Notch signaling is involved in many neurodegenerative diseases and brain disorders. Here, we summarize the fundamental role of Notch in neuronal development and specification and discuss how epigenetic regulation and pathway cross-talk contribute to Notch function. In addition, we cover aberrant alterations of Notch signaling in the diseased brain. The aim of this review is to provide an insight into how Notch signaling works in different contexts to control neurogenesis and its potential effects in diagnoses and therapies of neurodegeneration, brain tumors and disorders.
Rolando C, Erni A, Grison A, Beattie R, Engler A, Gokhale PJ, Milo M, Wegleiter T, Jessberger S, Taylor V.
Nov 3, 2016
Adult neural stem cells (NSCs) are defined by their inherent capacity to self-renew and give rise to neurons, astrocytes, and oligodendrocytes. In vivo, however, hippocampal NSCs do not generate oligodendrocytes for reasons that have remained enigmatic. Here, we report that deletion of Drosha in adult dentate gyrus NSCs activates oligodendrogenesis and reduces neurogenesis at the expense of gliogenesis. We further find that Drosha directly targets NFIB to repress its expression independently of Dicer and microRNAs. Knockdown of NFIB in Drosha-deficient hippocampal NSCs restores neurogenesis, suggesting that the Drosha/NFIB mechanism robustly prevents oligodendrocyte fate acquisition in vivo. Taken together, our findings establish that adult hippocampal NSCs inherently possess multilineage potential but that Drosha functions as a molecular barrier preventing oligodendrogenesis.
Drosha regulates adult hippocampal stem cell maintenance
Drosha inhibits oligodendrocytic differentiation of adult stem cells
Drosha targets NFIB mRNA hairpin to inhibit expression and enable neurogenesis
NFIB expression induces oligodendrocytic fate in adult hippocampal stem cells
Giachino C,Boulay JL,Ivanek R,Alvarado A,Tostado C,Lugert S,Tchorz J,Coban M,Mariani L,Bettler B,Lathia J,Frank S,Pfister S,Kool M, Taylor V
Dec 14, 2015
In the brain, Notch signaling maintains normal neural stem cells, but also brain cancer stem cells, indicating an oncogenic role. Here, we identify an unexpected tumor suppressor function for Notch in forebrain tumor subtypes. Genetic inactivation of RBP-Jk, a key Notch mediator, or Notch1 and Notch2 receptors accelerates PDGF-driven glioma growth in mice. Conversely, genetic activation of the Notch pathway reduces glioma growth and increases survival. In humans, high Notch activity strongly correlates with distinct glioma sub- types, increased patient survival, and lower tumor grade. Additionally, simultaneous inactivation of RBP- Jk and p53 induces primitive neuroectodermal-like tumors in mice. Hence, Notch signaling cooperates with p53 to restrict cell proliferation and tumor growth in mouse models of human brain tumours.
Notch signaling and p53 cooperate to reduce initiation of forebrain tumor subtypes
Anti-tumorigenic effects of Notch are linked to regulation of quiescence
Inhibiting Notch promotes a primitive neuroectodermal-like tumor fate
Low Notch activity correlates with poor prognosis for patients with glioma subtypes
Rolando, C., Taylor V.
Oct 7, 2014
The formation of the hippocampus is generated during embryonic development, but most neurons within the structure are produced after birth. The hippocampus is a primary region of neurogenesis within the adult mammalian brain. Adult-born neurons have to integrate into the established neural circuitry throughout life. Although the function of neurogenesis in the adult hippocampus, particularly in humans, remains unclear, experimental data suggest that adult-born neurons are involved in some forms of memory, as well as in diseases. Adult hippocampal neurogenesis is dynamic, responding to physiological and pathological stimuli that may promote brain function or contribute to diseases such as epilepsy. Here, we review some of the mechanisms and signaling pathways involved in the development of the hippocampus, as well as in adult neurogenesis. We discuss some recent findings suggesting heterogeneity within the hippocampal stem cell pool and the regulation of activation of quiescent stem cells. Finally, we discuss some of the issues relating neurogenesis to pathophysiology and aging.
Giachino C, Taylor V
Feb 25, 2014
Adult neural stem cells (NSCs) are perceived as a homogeneous population of cells that divide infrequently and are capable of multi-lineage differentiation. However, recent data revealed that independent stem cell lineages act in parallel to maintain neurogenesis and provide a cellular source for tissue repair. In addition, even within the same lineage, the stem and progenitor cells are strikingly heterogeneous including NSCs that are dormant or mitotically active. We will discuss these different NSC populations and activity states with relation to their role in neurogenesis and regeneration but also how these different stem cells respond to aging. NSCs depend on Notch signaling for their maintenance. While Notch-dependence is a common feature among NSC populations, we will discuss how differences in Notch signaling might contribute to adult NSC heterogeneity. Understanding the fate of multiple NSC populations with distinct functions has implications for the mechanisms of aging and regeneration.