Impaired Generation of Transit-Amplifying Progenitors in the Adult Subventricular Zone of Cyclin D2 Knockout Mice

In the adult brain, new neurons are constitutively derived from postnatal neural stem cells/progenitors located in two neurogenic regions: the subventricular zone (SVZ) of the lateral ventricles (migrating and differentiating into different subtypes of the inhibitory interneurons of the olfactory bulbs), and the subgranular layer of the hippocampal dentate gyrus. Cyclin D2 knockout (cD2-KO) mice exhibit reduced numbers of new hippocampal neurons; however, the proliferation deficiency and the dysregulation of adult neurogenesis in the SVZ required further investigation. In this report, we characterized the differentiation potential of each subpopulation of the SVZ neural precursors in cD2-KO mice. The number of newly generated cells in the SVZs was significantly decreased in cD2-KO mice compared to wild type mice (WT), and was not accompanied by elevated levels of apoptosis. Although the number of B1-type quiescent precursors (B1q) and the overall B1-type activated precursors (B1a) were not affected in the SVZ neurogenic niche, the number of transit-amplifying progenitors (TaPs) was significantly reduced. Additionally, the subpopulations of calbindin D28k and calretinin interneurons were diminished in the olfactory bulbs of cD2-KO mice. Our results suggest that cyclin D2 might be critical for the proliferation of neural precursors and progenitors in the SVZ—the transition of B1a into TaPs and, thereafter, the production of newly generated interneurons in the olfactory bulbs. Untangling regulators that functionally modulate adult neurogenesis provides a basis for the development of regenerative therapies for injuries and neurodegenerative diseases.

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Adult Neurogenesis: Lessons from Crayfish and the Elephant in the Room

Brain Behavior and Evolution ◽

10.1159/000447084 ◽

2016 ◽

Vol 87 (3) ◽

pp. 146-155 ◽

Cited By ~ 3

Author(s):

Barbara S. Beltz ◽

Georg Brenneis ◽

Jeanne L. Benton

Keyword(s):

Stem Cells ◽

Immune System ◽

Neural Stem Cells ◽

Adult Neurogenesis ◽

Adult Brain ◽

Neural Precursor ◽

Neural Precursors ◽

Neurogenic Niche ◽

Fetal Microchimerism ◽

The Brain

The 1st-generation neural precursors in the crustacean brain are functionally analogous to neural stem cells in mammals. Their slow cycling, migration of their progeny, and differentiation of their descendants into neurons over several weeks are features of the neural precursor lineage in crayfish that also characterize adult neurogenesis in mammals. However, the 1st-generation precursors in crayfish do not self-renew, contrasting with conventional wisdom that proposes the long-term self-renewal of adult neural stem cells. Nevertheless, the crayfish neurogenic niche, which contains a total of 200-300 cells, is never exhausted and neurons continue to be produced in the brain throughout the animal's life. The pool of neural precursors in the niche therefore cannot be a closed system, and must be replenished from an extrinsic source. Our in vitro and in vivo data show that cells originating in the innate immune system (but not other cell types) are attracted to and incorporated into the neurogenic niche, and that they express a niche-specific marker, glutamine synthetase. Further, labeled hemocytes that undergo adoptive transfer to recipient crayfish generate cells in neuronal clusters in the olfactory pathway of the adult brain. These hemocyte descendants express appropriate neurotransmitters and project to target areas typical of neurons in these regions. These studies indicate that under natural conditions, the immune system provides neural precursors supporting adult neurogenesis in the crayfish brain, challenging the canonical view that ectodermal tissues generating the embryonic nervous system are the sole source of neurons in the adult brain. However, these are not the first studies that directly implicate the immune system as a source of neural precursor cells. Several types of data in mammals, including adoptive transfers of bone marrow or stem cells as well as the presence of fetal microchimerism, suggest that there must be a population of cells that are able to access the brain and generate new neurons in these species.

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Relationships between dietary macronutrients and adult neurogenesis in the regulation of energy metabolism – CORRIGENDUM

British Journal Of Nutrition ◽

10.1017/s0007114513002869 ◽

2013 ◽

Vol 111 (4) ◽

pp. 755-755

Author(s):

Marianne A. Yon ◽

Suzanna L. Mauger ◽

Lucy C. Pickavance

Keyword(s):

Body Weight ◽

Energy Metabolism ◽

Adult Neurogenesis ◽

Brain Regions ◽

The Body ◽

Adult Brain ◽

Metabolic Dysfunction ◽

Neurogenic Niche ◽

Normal Limits ◽

Simple Carbohydrates

Of the environmental factors which have an impact on body weight, nutrients are most influential. Within normal limits, hypothalamic and related neuronal populations correct perturbations in energy metabolism, to return the body to its nutritional set-point, either through direct response to nutrients or indirectly via peripheral appetite signals. Excessive intake of certain macronutrients, such as simple carbohydrates and SFA, can lead to obesity and attendant metabolic dysfunction, also reflected in alterations in structural plasticity, and, intriguingly, neurogenesis, in some of these brain regions. Neurogenesis, previously thought to occur only in the embryo, is now known to take place in the adult brain, dependent on numerous stimulating and inhibiting factors, including dietary components. Because of classic associations between neurogenesis and the hippocampus, in learning and cognition, this brain region has also been the focus of attention in the study of links between diet and neurogenesis. Recently, however, a more complete picture of this relationship has been building: not only has the hypothalamus been shown to satisfy the criteria for a neurogenic niche, but appetite-related mediators, including circulating hormones, such as leptin and ghrelin, pro-inflammatory cytokines and the endocannabinoid intracellular messengers, are also being examined for their potential role in mediating neurogenic responses to macronutrients. The present review draws together these observations and investigates whether n-3 PUFA may exert their attenuating effects on body weight through the stimulation of adult neurogenesis. Exploration of the effects of nutraceuticals on neurogenic brain regions may encourage the development of new rational therapies in the fight against obesity.

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HPG-Dependent Peri-Pubertal Regulation of Adult Neurogenesis in Mice

Frontiers in Neuroanatomy ◽

10.3389/fnana.2020.584493 ◽

2020 ◽

Vol 14 ◽

Author(s):

Sara Trova ◽

Serena Bovetti ◽

Giuliana Pellegrino ◽

Sara Bonzano ◽

Paolo Giacobini ◽

...

Keyword(s):

Adult Neurogenesis ◽

Neural Plasticity ◽

Subventricular Zone ◽

Gonadal Hormones ◽

Sexually Dimorphic ◽

Social Stimuli ◽

Hpg Axis ◽

Neurogenic Niche ◽

Set Up ◽

Critical Developmental Period

Adult neurogenesis, a striking form of neural plasticity, is involved in the modulation of social stimuli driving reproduction. Previous studies on adult neurogenesis have shown that this process is significantly modulated around puberty in female mice. Puberty is a critical developmental period triggered by increased secretion of the gonadotropin releasing hormone (GnRH), which controls the activity of the hypothalamic-pituitary-gonadal axis (HPG). Secretion of HPG-axis factors at puberty participates to the refinement of neural circuits that govern reproduction. Here, by exploiting a transgenic GnRH deficient mouse model, that progressively loses GnRH expression during postnatal development (GnRH::Cre;DicerloxP/loxPmice), we found that a postnatally-acquired dysfunction in the GnRH system affects adult neurogenesis selectively in the subventricular-zone neurogenic niche in a sexually dimorphic way. Moreover, by examining adult females ovariectomized before the onset of puberty, we provide important evidence that, among the HPG-axis secreting factors, the circulating levels of gonadal hormones during pre-/peri-pubertal life contribute to set-up the proper adult subventricular zone-olfactory bulb neurogenic system.

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Neural Stem Cells in the Immature, but Not the Mature, Subventricular Zone Respond Robustly to Traumatic Brain Injury

Developmental Neuroscience ◽

10.1159/000367784 ◽

2014 ◽

Vol 37 (1) ◽

pp. 29-42 ◽

Cited By ~ 20

Author(s):

Matthew T. Goodus ◽

Alanna M. Guzman ◽

Frances Calderon ◽

Yuhui Jiang ◽

Steven W. Levison

Keyword(s):

Traumatic Brain Injury ◽

Stem Cells ◽

Flow Cytometry ◽

Brain Injury ◽

Neural Stem Cells ◽

Subventricular Zone ◽

Proliferative Response ◽

Fold Increase ◽

Adult Brain ◽

Neural Precursors

Pediatric traumatic brain injury is a significant problem that affects many children each year. Progress is being made in developing neuroprotective strategies to combat these injuries. However, investigators are a long way from therapies to fully preserve injured neurons and glia. To restore neurological function, regenerative strategies will be required. Given the importance of stem cells in repairing damaged tissues and the known persistence of neural precursors in the subventricular zone (SVZ), we evaluated regenerative responses of the SVZ to a focal brain lesion. As tissues repair more slowly with aging, injury responses of male Sprague Dawley rats at 6, 11, 17, and 60 days of age and C57Bl/6 mice at 14 days of age were compared. In the injured immature animals, cell proliferation in the dorsolateral SVZ more than doubled by 48 h. By contrast, the proliferative response was almost undetectable in the adult brain. Three approaches were used to assess the relative numbers of bona fide neural stem cells, as follows: the neurosphere assay (on rats injured at postnatal day 11, P11), flow cytometry using a novel 4-marker panel (on mice injured at P14) and staining for stem/progenitor cell markers in the niche (on rats injured at P17). Precursors from the injured immature SVZ formed almost twice as many spheres as precursors from uninjured age-matched brains. Furthermore, spheres formed from the injured brain were larger, indicating that the neural precursors that formed these spheres divided more rapidly. Flow cytometry revealed a 2-fold increase in the percentage of stem cells, a 4-fold increase in multipotential progenitor-3 cells and a 2.5-fold increase in glial-restricted progenitor-2/multipotential-3 cells. Analogously, there was a 2-fold increase in the mitotic index of nestin+/Mash1- immunoreactive cells within the immediately subependymal region. As the early postnatal SVZ is predominantly generating glial cells, an expansion of precursors might not necessarily lead to the production of many new neurons. On the contrary, many BrdU+/doublecortin+ cells were observed streaming out of the SVZ into the neocortex 2 weeks after injuries to P11 rats. However, very few new mature neurons were seen adjacent to the lesion 28 days after injury. Altogether, these data indicate that immature SVZ cells mount a more robust proliferative response to a focal brain injury than adult cells, which includes an expansion of stem cells, primitive progenitors and neuroblasts. Nonetheless, this regenerative response does not result in significant neuronal replacement, indicating that new strategies need to be implemented to retain the regenerated neurons and glia that are being produced.

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Adult neural stem cells have latent inflammatory potential that is kept suppressed by Tcf4 to facilitate adult neurogenesis

Science Advances ◽

10.1126/sciadv.abf5606 ◽

2021 ◽

Vol 7 (21) ◽

pp. eabf5606

Author(s):

Mohammad Shariq ◽

Vinaya Sahasrabuddhe ◽

Sreevatsan Krishna ◽

Swathi Radha ◽

Nruthyathi ◽

...

Keyword(s):

Stem Cells ◽

Transcription Factor ◽

Dentate Gyrus ◽

Adult Neurogenesis ◽

Neural Progenitors ◽

The Other ◽

Proliferative Capacity ◽

Differentiation Potential ◽

Neurogenic Niche ◽

Transcription Factor 4

Inflammation is known to adversely affect adult neurogenesis, wherein the source of inflammation is largely thought to be extraneous to the neurogenic niche. Here, we demonstrate that the adult hippocampal neural progenitors harbor an inflammatory potential that is proactively suppressed by transcription factor 4 (Tcf4). Deletion of Tcf4 in hippocampal nestin-expressing progenitors causes loss of proliferative capacity and acquisition of myeloid inflammatory properties. This transformation abolishes their differentiation potential and causes production of detrimental factors that adversely affect niche cells, causing inflammation in the dentate gyrus. Thus, on one hand, Tcf4 deletion causes abrogation of proliferative progenitors leading to reduction of adult neurogenesis, while on the other, their accompanying inflammatory transformation inflicts inflammation in the niche. Taken together, we provide the first evidence for a latent inflammatory potential of adult hippocampal neural progenitors and identify Tcf4 as a critical regulator that facilitates adult neurogenesis via proactive suppression of this detrimental potential.

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Characterization of neurogenic niches in the telencephalon of juvenile and adult sharks

10.1101/730721 ◽

2019 ◽

Author(s):

A Docampo-Seara ◽

S Pereira-Guldrís ◽

N Sánchez-Farías ◽

S Mazan ◽

MA Rodríguez ◽

...

Keyword(s):

Adult Neurogenesis ◽

Active Sites ◽

Ventricular Zone ◽

Adult Brain ◽

Mammalian Brain ◽

Stem Cell Markers ◽

Cell Markers ◽

Neurogenic Niche ◽

Glial Progenitors ◽

Multistep Process

AbstractNeurogenesis is a multistep process by which progenitor cells become terminally differentiated neurons. Adult neurogenesis has gathered increasing interest with the aim of developing new cell-based treatments for neurodegenerative diseases in humans. Active sites of adult neurogenesis exist from fish to mammals, although in the adult mammalian brain the number and extension of neurogenic areas is considerably reduced in comparison to non-mammalian vertebrates, and they become mostly reduced to the telencephalon. Much of our understanding in this field is based in studies on mammals and zebrafish, a modern bony fish. The use of the cartilaginous fish Scyliorhinus canicula (representative of basal gnathostomes) as a model expands the comparative framework to a species that shows highly neurogenic activity in the adult brain. In this work, we studied the proliferation pattern in the telencephalon of juvenile and adult specimens of S. canicula by using antibodies against the proliferation marker PCNA. We have characterized proliferating niches by using stem cell markers (Sox2), glial markers (GFAP, BLBP and GS), intermediate progenitor cell markers (Dlx2 and Tbr2) and markers for migrating neuroblasts (DCX). Based in the expression pattern of these markers, we demonstrate the existence of different cell subtypes within the PCNA immunoreactive zones including non-glial stem cells, glial progenitors, intermediate progenitor-like cells and migratory neuroblasts, which were widely distributed in the ventricular zone of the pallium, suggesting that the main progenitor types that constitute the neurogenic niche in mammals are already present in cartilaginous fishes.

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Adult Neurogenesis 2

10.1093/med/9780199729692.001.0001 ◽

2012 ◽

Cited By ~ 9

Author(s):

Gerd Kempermann, MD

Keyword(s):

Stem Cell ◽

Major Depression ◽

Adult Neurogenesis ◽

Subventricular Zone ◽

Cell Biology ◽

Adult Brain ◽

Historical Background ◽

Regulatory Mechanisms ◽

Stem Cell Biology ◽

The Subject

This resource is aimed at those interested in adult neurogenesis and stem cell biology of the adult brain, and covers the historical background and describes in detail adult neurogenesis in the hippocampus as well as the subventricular zone and olfactory bulb. It then discusses the regulatory mechanisms, and the subject of neurogenesis outside the "canonical" neurogenic regions of rodents and primates, as well as how adult neurogenesis in different species. It concludes with coverage of the provocative hypotheses that link failing adult neurogenesis with diseases such as temporal lobe epilepsy, major depression, schizophrenia, brain tumors, and dementias.

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Single-cell transcriptomics characterizes cell types in the subventricular zone and uncovers molecular defects underlying impaired adult neurogenesis

10.1101/365619 ◽

2018 ◽

Author(s):

Vera Zywitza ◽

Aristotelis Misios ◽

Lena Bunatyan ◽

Thomas E. Willnow ◽

Nikolaus Rajewsky

Keyword(s):

Single Cell ◽

Adult Neurogenesis ◽

Subventricular Zone ◽

Single Cells ◽

Cell Types ◽

Neural Cell ◽

Adult Brain ◽

List Type ◽

Cell Type ◽

Cell Type Specific

SUMMARYNeural stem cells (NSCs) contribute to plasticity and repair of the adult brain. Niches harboring NSCs are crucial for regulating stem cell self-renewal and differentiation. We used single-cell RNA profiling to generate an unbiased molecular atlas of all cell types in the largest neurogenic niche of the adult mouse brain, the subventricular zone (SVZ). We characterized > 20 neural and non-neural cell types and gained insights into the dynamics of neurogenesis by predicting future cell states based on computational analysis of RNA kinetics. Furthermore, we apply our single-cell approach to mice lacking LRP2, an endocytic receptor required for SVZ maintenance. The number of NSCs and proliferating progenitors was significantly reduced. Moreover, Wnt and BMP4 signaling was perturbed. We provide a valuable resource for adult neurogenesis, insights into SVZ neurogenesis regulation by LRP2, and a proof-of-principle demonstrating the power of single-cell RNA-seq in pinpointing neural cell type-specific functions in loss-of-function models.HIGHLIGHTSunbiased single-cell transcriptomics characterizes adult NSCs and their nichecell type-specific signatures and marker genes for 22 SVZ cell typesFree online tool to assess gene expression across 9,804 single cellscell type-specific dysfunctions underlying impaired adult neurogenesis

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Subventricular zone/white matter microglia reconstitute the empty adult microglial niche in a dynamic wave

10.1101/2021.02.17.431594 ◽

2021 ◽

Author(s):

Lindsay A. Hohsfield ◽

Allison R. Najafi ◽

Yasamine Ghorbanian ◽

Neelakshi Soni ◽

Joshua D. Crapser ◽

...

Keyword(s):

White Matter ◽

Subventricular Zone ◽

Myeloid Cells ◽

Myeloid Cell ◽

Distinct Pattern ◽

Adult Brain ◽

Cell Dynamics ◽

Neurogenic Niche ◽

Functional Profiles ◽

Dynamic Wave

AbstractMicroglia, the brain’s resident myeloid cells, play central roles in brain defense, homeostasis, and disease. Using sustained colony-stimulating factor 1 receptor inhibition, we report an unprecedented level of microglial depletion and establish a model system that achieves an empty microglial niche in the adult brain. We identify a myeloid cell that migrates from an important neurogenic niche, the subventricular zone, and associated white matter areas. These cells exhibit tremendous chemotaxis potential, migrating radially and tangentially in a dynamic wave and filling the brain in a distinct pattern, to fully replace the microglial-depleted brain. These repopulating cells are enriched in disease-associated microglia genes and exhibit distinct phenotypic and functional profiles to endogenous microglia. Our findings shed light on the overlapping and distinct functional complexity and diversity of myeloid cells of the CNS and provide new insight into myeloid cell dynamics in an empty microglial niche without contributions from bone marrow-derived cells.

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The critical role of cyclin D2 in adult neurogenesis

The Journal of Cell Biology ◽

10.1083/jcb.200404181 ◽

2004 ◽

Vol 167 (2) ◽

pp. 209-213 ◽

Cited By ~ 113

Author(s):

Anna Kowalczyk ◽

Robert K. Filipkowski ◽

Marcin Rylski ◽

Grzegorz M. Wilczynski ◽

Filip A. Konopacki ◽

...

Keyword(s):

Dentate Gyrus ◽

Adult Neurogenesis ◽

Molecular Mechanisms ◽

Regulatory Gene ◽

Critical Role ◽

Brain Structures ◽

Adult Brain ◽

Cyclin D2 ◽

Genetic Ablation ◽

Neuronal Precursors

Adult neurogenesis (i.e., proliferation and differentiation of neuronal precursors in the adult brain) is responsible for adding new neurons in the dentate gyrus of the hippocampus and in the olfactory bulb. We describe herein that adult mice mutated in the cell cycle regulatory gene Ccnd2, encoding cyclin D2, lack newly born neurons in both of these brain structures. In contrast, genetic ablation of cyclin D1 does not affect adult neurogenesis. Furthermore, we show that cyclin D2 is the only D-type cyclin (out of D1, D2, and D3) expressed in dividing cells derived from neuronal precursors present in the adult hippocampus. In contrast, all three cyclin D mRNAs are present in the cultures derived from 5-day-old hippocampi, when developmental neurogenesis in the dentate gyrus takes place. Thus, our results reveal the existence of molecular mechanisms discriminating adult versus developmental neurogeneses.

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