Helena Mira

Regulation of Neurogenesis by Neurotrophins during Adulthood: Expected and Unexpected Roles

The subventricular zone (SVZ) of the anterolateral ventricle and the subgranular zone (SGZ) of the hippocampal dentate gyrus are the two main regions of the adult mammalian brain in which neurogenesis is maintained throughout life. Because alterations in adult neurogenesis appear to be a common hallmark of different neurodegenerative diseases, understanding the molecular mechanisms controlling adult neurogenesis is a focus of active research. Neurotrophic factors are a family of molecules that play critical roles in the survival and differentiation of neurons during development and in the control of neural plasticity in the adult. Several neurotrophins and neurotrophin receptors have been implicated in the regulation of adult neurogenesis at different levels. Here, we review the current understanding of neurotrophin modulation of adult neurogenesis in both the SVZ and SGZ. We compile data supporting a variety of roles for neurotrophins/neurotrophin receptors in different scenarios, including both expected and unexpected functions.

MicroRNAs as Regulators of Neural Stem Cell-Related Pathways in Glioblastoma Multiforme

MicroRNAs are endogenous non-coding small RNAs that have been described as highly conserved regulators of gene expression. They are involved in cancer and in the regulation of neural development and stem cell function. Recent studies suggest that a small subpopulation of cancer stem cells (CSCs) has the capacity to repopulate solid tumours such as glioblastoma (GBM), drive malignant progression and mediate radio- and chemoresistance. GBM-derived CSCs share the fundamental stem cell properties of self-renewal and multipotency with neural stem cells (NSCs) and may be regulated by miRNAs. In this review, we will summarize the current knowledge regarding the role of miRNAs in GBM development with a focus on the regulation of GBM-CSCs. We propose a list of miRNAs that could serve as molecular classifiers for GBMs and/or as promising therapeutic targets for such brain tumours.

The Cyclin‐Dependent Kinase Inhibitor p27kip1 Regulates Radial Stem Cell Quiescence and Neurogenesis in the Adult Hippocampus

Members of the cyclin‐dependent kinase (CDK)‐inhibitory protein (CIP)/kinase‐inhibitory protein (KIP) family of cyclin‐dependent kinase inhibitors regulate proliferation and cell cycle exit of mammalian cells. In the adult brain, the CIP/KIP protein p27kip1 has been related to the regulation of intermediate progenitor cells located in neurogenic niches. Here, we uncover a novel function of p27kip1 in the adult hippocampus as a dual regulator of stem cell quiescence and of cell‐cycle exit of immature neurons. In vivo, p27kip1 is detected in radial stem cells expressing SOX2 and in newborn neurons of the dentate gyrus. In vitro, the Cdkn1b gene encoding p27kip1 is transcriptionally upregulated by quiescence signals such as BMP4. The nuclear accumulation of p27kip1 protein in adult hippocampal stem cells encompasses the BMP4‐induced quiescent state and its overexpression is able to block proliferation. p27kip1 is also expressed in immature neurons upon differentiation of adult hippocampal stem cell cultures. Loss of p27kip1 leads to an increase in proliferation and neurogenesis in the adult dentate gyrus, which results from both a decrease in the percentage of radial stem cells that are quiescent and a delay in cell cycle exit of immature neurons. Analysis of animals carrying a disruption in the cyclin‐CDK interaction domain of p27kip1 indicates that the CDK inhibitory function of the protein is necessary to control the activity of radial stem cells. Thus, we report that p27kip1 acts as a central player of the molecular program that keeps adult hippocampal stem cells out of the cell cycle. Stem Cells 2015;33:219–229

Aβ increases neural stem cell activity in senescence-accelerated SAMP8 mice.

Neurogenesis persists in the adult brain as a form of plasticity due to the existence of neural stem cells (NSCs). Alterations in neurogenesis have been found in transgenic Alzheimers disease (AD) mouse models, but NSC activity and neurogenesis in sporadic AD models remains to be examined. We herein describe a remarkable increase in NSC proliferation in the forebrain of SAMP8, a non-transgenic mouse strain that recapitulates the transition from healthy aging to AD. The increase in proliferation is transient, precedes AD-like symptoms such as amyloid beta 1-42 [Aβ(1-42)] increase or gliosis, and is followed by a steep decline at later stages. Interestingly, in vitro studies indicate that secreted Aβ(1-42) and PI3K signaling may account for the early boost in NSC proliferation. Our results highlight the role of soluble Aβ(1-42) peptide and PI3K in the autocrine regulation of NSCs, and further suggest that over-proliferation of NSCs before the appearance of AD pathology may underlie neurogenic failure during the age-related progression of the disease. These findings have implications for therapeutic approaches based on neurogenesis in AD.

Symmetric Expansion of Neural Stem Cells from the Adult Olfactory Bulb Is Driven by Astrocytes Via WNT7A

Adult neural stem cells (NSCs) located in the subventricular zone (SVZ) persistently produce new neurons destined to the olfactory bulb (OB). Recent research suggests that the OB is also a source of NSCs that remains largely unexplored. Using single/dual‐labeling procedures, we address the existence of NSCs in the innermost layers of the OB. In vivo, these cells are more quiescent that their SVZ counterparts, but after in vitro expansion, they behave similarly. Self‐renewal and proliferation assays in co‐culture with niche astrocytes indicate that OB‐glia restricts NSC activity whereas SVZ‐glia has the opposite effect. Gene expression profiling identifies WNT7A as a key SVZ‐glial factor lacking in OB‐glia that enhances self‐renewal, thereby improving the propagation of OB‐NSC cultures. These data demonstrate that region‐specific glial factors account for in vivo differences in NSC activity and point to WNT7A as a tool that may be instrumental for the NSC expansion phase that precedes grafting. STEM CELLS 2012;30:2796–2809

BMPs as Therapeutic Targets and Biomarkers in Astrocytic Glioma

Astrocytic glioma is the most common brain tumor. The glioma initiating cell (GIC) fraction of the tumor is considered as highly chemoresistant, suggesting that GICs are responsible for glioma relapse. A potential treatment for glioma is to induce differentiation of GICs to a more benign and/or druggable cell type. Given BMPs are among the most potent inducers of GIC differentiation, they have been considered as noncytotoxic therapeutic compounds that may be of use to prevent growth and recurrence of glioma. We herein summarize advances made in the understanding of the role of BMP signaling in astrocytic glioma, with a particular emphasis on the effects exerted on GICs. We discuss the prognostic value of BMP signaling components and the implications of BMPs in the differentiation of GICs and in their sensitization to alkylating drugs and oncolytic therapy/chemotherapy. This mechanistic insight may provide new opportunities for therapeutic intervention of brain cancer.

Control of Adult Neurogenesis by Short-Range Morphogenic-Signaling Molecules

Adult neurogenesis is dynamically regulated by a tangled web of local signals emanating from the neural stem cell (NSC) microenvironment. Both soluble and membrane-bound niche factors have been identified as determinants of adult neurogenesis, including morphogens. Here, we review our current understanding of the role and mechanisms of short-range morphogen ligands from the Wnt, Notch, Sonic hedgehog, and bone morphogenetic protein (BMP) families in the regulation of adult neurogenesis. These morphogens are ideally suited to fine-tune stem-cell behavior, progenitor expansion, and differentiation, thereby influencing all stages of the neurogenesis process. We discuss cross talk between their signaling pathways and highlight findings of embryonic development that provide a relevant context for understanding neurogenesis in the adult brain. We also review emerging examples showing that the web of morphogens is in fact tightly linked to the regulation of neurogenesis by diverse physiologic processes.

Single and Dual Birthdating Procedures for Assessing the Response of Adult Neural Stem Cells to the Infusion of a Soluble Factor Using Halogenated Thymidine Analogs

The factors that regulate the switch from adult neural stem cell (aNSC) quiescence to active proliferation are poorly understood. Here we describe a method to study the in vivo effect of a soluble factor on cell cycle entry and proliferation of aNSCs located in the brain neurogenic niches. First, we provide information for implanting osmotic minipumps that will deliver the compound of interest directly into the mouse brain. When combined with the administration of the thymidine analog bromodeoxyuridine (BrdU), this technique is the most basic procedure to study the effects of a soluble factor on aNSC proliferation. We also describe a dual replication labeling protocol using two different halogenated thymidine analogs, chloro- and iododeoxyuridine (CldU and IdU), that allows tracking of proliferating cells and assessing cell cycle re-entry of aNSCs at different time points.

Noggin rescues age-related stem cell loss in the brain of senescent mice with neurodegenerative pathology

Significance Alzheimer’s disease (AD) is the most common cause of age-related neurodegeneration. Damage initially occurs in the hippocampus, a neurogenic brain region essential in forming memories. Since there is no cure for AD, therapeutic strategies that may aid to slow hippocampal dysfunction are necessary. We describe the precocious hippocampal stem cell loss of a mouse model that mimics the onset of pathological AD-like neurodegeneration. The loss is due to an increase in BMP6 that limits neurogenesis. We demonstrate that blocking BMP signaling by means of Noggin administration is beneficial to the hippocampal microenvironment, restoring stem cell numbers, neurogenesis, and behavior. Our findings support further development of BMP antagonists into translatable molecules for the rescue of stem cells and neurogenesis in neurodegeneration/aging. Increasing age is the greatest known risk factor for the sporadic late-onset forms of neurodegenerative disorders such as Alzheimer’s disease (AD). One of the brain regions most severely affected in AD is the hippocampus, a privileged structure that contains adult neural stem cells (NSCs) with neurogenic capacity. Hippocampal neurogenesis decreases during aging and the decrease is exacerbated in AD, but the mechanistic causes underlying this progressive decline remain largely unexplored. We here investigated the effect of age on NSCs and neurogenesis by analyzing the senescence accelerated mouse prone 8 (SAMP8) strain, a nontransgenic short-lived strain that spontaneously develops a pathological profile similar to that of AD and that has been employed as a model system to study the transition from healthy aging to neurodegeneration. We show that SAMP8 mice display an accelerated loss of the NSC pool that coincides with an aberrant rise in BMP6 protein, enhanced canonical BMP signaling, and increased astroglial differentiation. In vitro assays demonstrate that BMP6 severely impairs NSC expansion and promotes NSC differentiation into postmitotic astrocytes. Blocking the dysregulation of the BMP pathway and its progliogenic effect in vivo by intracranial delivery of the antagonist Noggin restores hippocampal NSC numbers, neurogenesis, and behavior in SAMP8 mice. Thus, manipulating the local microenvironment of the NSC pool counteracts hippocampal dysfunction in pathological aging. Our results shed light on interventions that may allow taking advantage of the brain’s natural plastic capacity to enhance cognitive function in late adulthood and in chronic neurodegenerative diseases such as AD.