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1.
Neural Regen Res ; 17(11): 2472-2483, 2022 Nov.
Article in English | MEDLINE | ID: mdl-35535899

ABSTRACT

The mechanisms that regulate neural stem cell (NSC) lineage progression and maintain NSCs within different domains of the adult neural stem cell niche, the subventricular zone are not well defined. Quiescent NSCs are arranged at the apical ventricular wall, while mitotically activated NSCs are found in the basal, vascular region of the subventricular zone. Here, we found that ADAM10 (a disintegrin and metalloproteinase 10) is essential in NSC association with the ventricular wall, and via this adhesion to the apical domain, ADAM10 regulates the switch from quiescent and undifferentiated NSC to an actively proliferative and differentiating cell state. Processing of JAMC (junctional adhesion molecule C) by ADAM10 increases Rap1GAP activity. This molecular machinery promotes NSC transit from the apical to the basal compartment and subsequent lineage progression. Understanding the molecular mechanisms responsible for regulating the proper positioning of NSCs within the subventricular zone niche and lineage progression of NSCs could provide new targets for drug development to enhance the regenerative properties of neural tissue.

3.
Nat Commun ; 9(1): 36, 2018 01 02.
Article in English | MEDLINE | ID: mdl-29296000

ABSTRACT

Adult neural stem cells (NSCs) reside in a specialized microenvironment, the subventricular zone (SVZ), which provides them with unique signaling cues to control their basic properties and prevent their exhaustion. While the signaling mechanisms that regulate NSC lineage progression are well characterized, the molecular mechanisms that trigger the activation of quiescent NSCs during homeostasis and tissue repair are still unclear. Here, we uncovered that the NSC quiescent state is maintained by Rho-GTPase Cdc42, a downstream target of non-canonical Wnt signaling. Mechanistically, activation of Cdc42 induces expression of molecules involved in stem cell identity and anchorage to the niche. Strikingly, during a demyelination injury, downregulation of non-canonical Wnt-dependent Cdc42 activity is necessary to promote activation and lineage progression of quiescent NSCs, thereby initiating the process of tissue repair.


Subject(s)
Demyelinating Diseases , Homeostasis , Neural Stem Cells/cytology , Signal Transduction , Wnt Proteins/metabolism , Animals , cdc42 GTP-Binding Protein/metabolism
4.
Neuron ; 88(5): 941-956, 2015 Dec 02.
Article in English | MEDLINE | ID: mdl-26606998

ABSTRACT

NG2-expressing glia (NG2 glia) are a uniformly distributed and mitotically active pool of cells in the central nervous system (CNS). In addition to serving as progenitors of myelinating oligodendrocytes, NG2 glia might also fulfill physiological roles in CNS homeostasis, although the mechanistic nature of such roles remains unclear. Here, we report that ablation of NG2 glia in the prefrontal cortex (PFC) of the adult brain causes deficits in excitatory glutamatergic neurotransmission and astrocytic extracellular glutamate uptake and induces depressive-like behaviors in mice. We show in parallel that chronic social stress causes NG2 glia density to decrease in areas critical to Major Depressive Disorder (MDD) pathophysiology at the time of symptom emergence in stress-susceptible mice. Finally, we demonstrate that loss of NG2 glial secretion of fibroblast growth factor 2 (FGF2) suffices to induce the same behavioral deficits. Our findings outline a pathway and role for NG2 glia in CNS homeostasis and mood disorders.


Subject(s)
Antigens/metabolism , Depression/pathology , Fibroblast Growth Factor 2/metabolism , Neuroglia/metabolism , Prefrontal Cortex/pathology , Proteoglycans/metabolism , Stress, Psychological/physiopathology , Amino Acid Transport System X-AG/genetics , Amino Acid Transport System X-AG/metabolism , Animals , Antigens/genetics , Depression/etiology , Diphtheria Toxin/administration & dosage , Disease Models, Animal , Down-Regulation/genetics , Exploratory Behavior/physiology , Fibroblast Growth Factor 2/genetics , Heparin-binding EGF-like Growth Factor/genetics , Humans , Membrane Potentials/drug effects , Membrane Potentials/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Neurons/drug effects , Neurons/metabolism , Phosphopyruvate Hydratase/metabolism , Protein Transport/drug effects , Protein Transport/genetics , Proteoglycans/genetics , Receptors, Glutamate/genetics , Receptors, Glutamate/metabolism , Signal Transduction/drug effects , Signal Transduction/genetics , Synaptic Transmission/drug effects , Synaptic Transmission/genetics
5.
J Neurosci ; 35(35): 12241-7, 2015 09 02.
Article in English | MEDLINE | ID: mdl-26338334

ABSTRACT

UNLABELLED: The identification of the molecular network that supports oligodendrocyte (OL) regeneration under demyelinating conditions has been a primary goal for regenerative medicine in demyelinating disorders. We recently described an essential function for TACE/ADAM17 in regulating oligodendrogenesis during postnatal myelination, but it is unknown whether this protein also plays a role in OL regeneration and remyelination under demyelinating conditions. By using genetic mouse models to achieve selective gain- or loss-of-function of TACE or EGFR in OL lineage cells in vivo, we found that TACE is critical for EGFR activation in OLs following demyelination, and therefore, for sustaining OL regeneration and CNS remyelination. TACE deficiency in oligodendrocyte progenitor cells following demyelination disturbs OL lineage cell expansion and survival, leading to a delay in the remyelination process. EGFR overexpression in TACE deficient OLs in vivo restores OL development and postnatal CNS myelination, but also OL regeneration and CNS remyelination following demyelination. Our study reveals an essential function of TACE in supporting OL regeneration and CNS remyelination that may contribute to the design of new strategies for therapeutic intervention in demyelinating disorders by promoting oligodendrocyte regeneration and myelin repair. SIGNIFICANCE STATEMENT: Oligodendrocyte (OL) regeneration has emerged as a promising new approach for the treatment of demyelinating disorders. By using genetic mouse models to selectively delete TACE expression in oligodendrocyte progenitors cells (OPs), we found that TACE/ADAM17 is required for supporting OL regeneration following demyelination. TACE genetic depletion in OPs abrogates EGFR activation in OL lineage cells, and perturbs cell expansion and survival, blunting the process of CNS remyelination. Moreover, EGFR overexpression in TACE-deficient OPs in vivo overcomes the defects in OL development during postnatal development but also OL regeneration during CNS remyelination. Our study identifies TACE as an essential player in OL regeneration that may provide new insights in the development of new strategies for promoting myelin repair in demyelinating disorders.


Subject(s)
ADAM Proteins/metabolism , Central Nervous System/pathology , Demyelinating Diseases/pathology , Gene Expression Regulation/physiology , Multiple Sclerosis/pathology , Oligodendroglia/physiology , Regeneration/physiology , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase/genetics , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase/metabolism , ADAM17 Protein , Animals , Antigens/genetics , Antigens/metabolism , Cell Lineage/drug effects , Cell Lineage/genetics , Demyelinating Diseases/chemically induced , Disease Models, Animal , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Expression Regulation/drug effects , Luminescent Proteins/genetics , Luminescent Proteins/metabolism , Mice , Mice, Transgenic , Oligodendroglia/drug effects , Oligodendroglia/ultrastructure , Proteoglycans/genetics , Proteoglycans/metabolism , Receptor, Platelet-Derived Growth Factor alpha/genetics , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Regeneration/drug effects
6.
J Neurosci ; 35(17): 6946-51, 2015 Apr 29.
Article in English | MEDLINE | ID: mdl-25926469

ABSTRACT

Neuron-glial antigen 2-positive (NG2(+)) glial cells are the most proliferative glia type in the adult CNS, and their tile-like arrangement in adult gray matter is under tight regulation. However, little is known about the cues that govern this unique distribution. To this end, using a NG2(+) glial cell ablation model in mice, we examined the repopulation dynamics of NG2(+) glial cells in the mature and aged mice gray matter. We found that some resident NG2(+) glial cells that escaped depletion rapidly enter the cell cycle to repopulate the cortex with altered spatial distribution. We reveal that netrin-1 signaling is involved in the NG2(+) glial cell early proliferative, late repopulation, and distribution response after ablation in the gray matter. However, ablation of NG2(+) glial cell in older animals failed to stimulate a similar repopulation response, possibly because of a decrease in the sensitivity to netrin-1. Our findings indicate that endogenous netrin-1 plays a role in NG2(+) glial cell homeostasis that is distinct from its role in myelination.


Subject(s)
Aging , Antigens/metabolism , Gray Matter/cytology , Homeostasis/physiology , Nerve Growth Factors/metabolism , Neuroglia/metabolism , Proteoglycans/metabolism , Signal Transduction/physiology , Tumor Suppressor Proteins/metabolism , Animals , Antibodies/pharmacology , Antigens/genetics , Bromodeoxyuridine/metabolism , Cell Count , Homeostasis/drug effects , Immunoprecipitation , Ki-67 Antigen/metabolism , Mice, Transgenic , Microscopy, Confocal , Nerve Growth Factors/immunology , Netrin-1 , Neuroglia/drug effects , Proliferating Cell Nuclear Antigen/metabolism , Proteoglycans/genetics , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Receptor, Platelet-Derived Growth Factor alpha/metabolism , Signal Transduction/drug effects , Tumor Suppressor Proteins/immunology
7.
J Neurosci ; 34(36): 11884-96, 2014 09 03.
Article in English | MEDLINE | ID: mdl-25186737

ABSTRACT

Several studies have elucidated the significance of a disintegrin and metalloproteinase proteins (ADAMs) in PNS myelination, but there is no evidence if they also play a role in oligodendrogenesis and CNS myelination. Our study identifies ADAM17, also called tumor necrosis factor-α converting enzyme (TACE), as a novel key modulator of oligodendrocyte (OL) development and CNS myelination. Genetic deletion of TACE in oligodendrocyte progenitor cells (OPs) induces premature cell cycle exit and reduces OL cell survival during postnatal myelination of the subcortical white matter (SCWM). These cellular and molecular changes lead to deficits in SCWM myelination and motor behavior. Mechanistically, TACE regulates oligodendrogenesis by modulating the shedding of EGFR ligands TGFα and HB-EGF and, consequently, EGFR signaling activation in OL lineage cells. Constitutive TACE depletion in OPs in vivo leads to similar alterations in CNS myelination and motor behavior as to what is observed in the EGFR hypofunctional mouse line EgfrWa2. EGFR overexpression in TACE-deficient OPs restores OL survival and development. Our study reveals an essential function of TACE in oligodendrogenesis, and demonstrates how this molecule modulates EGFR signaling activation to regulate postnatal CNS myelination.


Subject(s)
ADAM Proteins/metabolism , Brain/metabolism , Myelin Sheath/metabolism , Neurogenesis , Oligodendroglia/metabolism , ADAM Proteins/genetics , ADAM17 Protein , Animals , Brain/growth & development , Brain/physiology , Cell Line , Cell Lineage , Cells, Cultured , ErbB Receptors/genetics , ErbB Receptors/metabolism , Heparin-binding EGF-like Growth Factor , Intercellular Signaling Peptides and Proteins/metabolism , Locomotion , Mice , Neural Stem Cells/cytology , Neural Stem Cells/metabolism , Oligodendroglia/cytology , Transforming Growth Factor alpha/metabolism
8.
J Neurosci ; 34(29): 9590-606, 2014 07 16.
Article in English | MEDLINE | ID: mdl-25031401

ABSTRACT

Discrete cellular microenvironments regulate stem cell pools and their development, as well as function in maintaining tissue homeostasis. Although the signaling elements modulating neural progenitor cells (NPCs) of the adult subventricular zone (SVZ) niche are fairly well understood, the pathways activated following injury and the resulting outcomes, are less clear. In the present study, we used mouse models of demyelination and proteomics analysis to identify molecular cues present in the adult SVZ niche during injury, and analyzed their role on NPCs in the context of promoting myelin repair. Proteomic analysis of SVZ tissue from mice with experimental demyelination identified several proteins that are known to play roles in NPC proliferation, adhesion, and migration. Among the proteins found to be upregulated were members of the N-cadherin signaling pathway. During the onset of demyelination in the subcortical white matter (SCWM), activation of epidermal growth factor receptor (EGFR) signaling in SVZ NPCs stimulates the interaction between N-cadherin and ADAM10. Upon cleavage and activation of N-cadherin signaling by ADAM10, NPCs undergo cytoskeletal rearrangement and polarization, leading to enhanced migration out of the SVZ into demyelinated lesions of the SCWM. Genetically disrupting either EGFR signaling or ADAM10 inhibits this pathway, preventing N-cadherin regulated NPC polarization and migration. Additionally, in vivo experiments using N-cadherin gain- and loss-of-function approaches demonstrated that N-cadherin enhances the recruitment of SVZ NPCs into demyelinated lesions. Our data revealed that EGFR-dependent N-cadherin signaling physically initiated by ADAM10 cleavage is the response of the SVZ niche to promote repair of the injured brain.


Subject(s)
Cadherins/metabolism , Cell Movement/physiology , Gene Expression Regulation/physiology , Lateral Ventricles/cytology , Neural Stem Cells/physiology , Recovery of Function/physiology , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase/genetics , 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase/metabolism , Animals , Antigens/genetics , Antigens/metabolism , Cadherins/genetics , Cell Adhesion/drug effects , Cell Adhesion/genetics , Cell Movement/drug effects , Demyelinating Diseases/chemically induced , Disease Models, Animal , Epidermal Growth Factor/pharmacology , Gene Expression Regulation/drug effects , Mice , Mice, Transgenic , Myelin Proteins/genetics , Myelin Proteins/metabolism , Organ Culture Techniques , Proteoglycans/genetics , Proteoglycans/metabolism , Proteomics , Recovery of Function/drug effects , Recovery of Function/genetics , Signal Transduction/drug effects , Signal Transduction/genetics , Time Factors , Wiskott-Aldrich Syndrome Protein Family/genetics , Wiskott-Aldrich Syndrome Protein Family/metabolism
9.
J Neurosci ; 34(23): 7917-30, 2014 06 04.
Article in English | MEDLINE | ID: mdl-24899714

ABSTRACT

Research on myelination has focused on identifying molecules capable of inducing oligodendrocyte (OL) differentiation in an effort to develop strategies that promote functional myelin regeneration in demyelinating disorders. Here, we show that transforming growth factor ß (TGFß) signaling is crucial for allowing oligodendrocyte progenitor (OP) cell cycle withdrawal, and therefore, for oligodendrogenesis and postnatal CNS myelination. Enhanced oligodendrogenesis and subcortical white matter (SCWM) myelination was detected after TGFß gain of function, while TGFß receptor II (TGFß-RII) deletion in OPs prevents their development into mature myelinating OLs, leading to SCWM hypomyelination in mice. TGFß signaling modulates OP cell cycle withdrawal and differentiation through the transcriptional modulation of c-myc and p21 gene expression, mediated by the interaction of SMAD3/4 with Sp1 and FoxO1 transcription factors. Our study is the first to demonstrate an autonomous and crucial role of TGFß signaling in OL development and CNS myelination, and may provide new avenues in the treatment of demyelinating diseases.


Subject(s)
Cell Cycle/physiology , Central Nervous System/metabolism , Myelin Sheath/metabolism , Oligodendroglia/physiology , Signal Transduction/physiology , Stem Cells/physiology , Transforming Growth Factor beta/metabolism , Age Factors , Animals , Animals, Newborn , Benzamides/pharmacology , Cell Cycle/drug effects , Cells, Cultured , Central Nervous System/cytology , Dioxoles/pharmacology , Forkhead Box Protein O1 , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/metabolism , Gene Expression Regulation, Developmental/genetics , Immunoglobulins/genetics , Immunoglobulins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oligodendroglia/drug effects , Signal Transduction/drug effects , Smad3 Protein/genetics , Smad3 Protein/metabolism , Stem Cells/drug effects
10.
Neuron ; 81(3): 588-602, 2014 Feb 05.
Article in English | MEDLINE | ID: mdl-24507193

ABSTRACT

Oligodendrocyte progenitor cells (OPCs) can repair demyelinated lesions by maturing into myelin-producing oligodendrocytes. However, the OPC potential to differentiate can be prevented by inhibitory signals present in the pathological lesion environment. Identification of these signals is essential to promote OPC differentiation and lesion repair. We identified an endogenous inhibitor of remyelination, Endothelin-1 (ET-1), which is highly expressed in reactive astrocytes of demyelinated lesions. Using both gain- and loss-of-function approaches, we demonstrate that ET-1 drastically reduces the rate of remyelination. We also discovered that ET-1 acts mechanistically by promoting Notch activation in OPCs during remyelination through induction of Jagged1 expression in reactive astrocytes. Pharmacological inhibition of ET signaling prevented Notch activation in demyelinated lesions and accelerated remyelination. These findings reveal that ET-1 is a negative regulator of OPC differentiation and remyelination and is potentially a therapeutic target to promote lesion repair in demyelinated tissue.


Subject(s)
Astrocytes/metabolism , Demyelinating Diseases/pathology , Endothelin-1/metabolism , Gene Expression Regulation/physiology , Receptors, Notch/metabolism , Animals , Astrocytes/drug effects , Astrocytes/ultrastructure , Calcium-Binding Proteins/metabolism , Cell Count , Cell Differentiation/drug effects , Demyelinating Diseases/chemically induced , Demyelinating Diseases/drug therapy , Demyelinating Diseases/metabolism , Disease Models, Animal , Drug Delivery Systems , Endothelin-1/adverse effects , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Glial Fibrillary Acidic Protein/genetics , Green Fluorescent Proteins/genetics , Intercellular Signaling Peptides and Proteins/metabolism , Jagged-1 Protein , Lipopolysaccharides/pharmacology , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Mice, Transgenic , Oligopeptides/pharmacology , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Serrate-Jagged Proteins , Stem Cells/drug effects , Stem Cells/physiology
12.
ASN Neuro ; 5(5): e00130, 2013 Dec 23.
Article in English | MEDLINE | ID: mdl-24286475

ABSTRACT

The Notch pathway is a highly conserved signaling system essential for modulating neurogenesis and promoting astrogenesis. Similarly, the cAMP signaling cascade can promote astrocytic commitment in several cell culture models, such as the C6 glioma cell line. These cells have the capacity to differentiate into oligodendrocytes or astrocytes, characteristics that allow their use as a glial progenitor model. In this context, we explore here the plausible involvement of cAMP in Notch-dependent signal transactions. The exposure of C6 cells to a non-hydrolysable cAMP analogue resulted in a sustained augmentation of Notch activity, as detected by nuclear translocation of its intracellular domain portion (NICD) and transcriptional activity. The cAMP effect is mediated through the activation of the γ-secretase complex, responsible for Notch cleavage and is sensitive to inhibitors of the cAMP-dependent protein kinase, PKA. As expected, Notch cleavage and nuclear translocation resulted in the up-regulation of the mRNA levels of one of its target genes, the transcription factor Hair and enhancer of split 5. Moreover, the glutamate uptake activity, as well as the expression of astrocytic markers such as glial fibrillary acidic protein, S100ß protein and GLAST was also enhanced in cAMP-exposed cells. Our results clearly suggest that during the process of C6 astrocytic differentiation, cAMP activates the PKA/γ-secretase/NICD/RBPJ(κ) pathway and Notch1 expression, leading to transcriptional activation of the genes responsible for glial progenitor cell fate decision.


Subject(s)
Astrocytes/cytology , Cell Differentiation/physiology , Intracellular Membranes/metabolism , Receptors, Notch/metabolism , Signal Transduction/physiology , Up-Regulation/physiology , Adjuvants, Immunologic/pharmacology , Animals , Astrocytes/drug effects , Astrocytoma/pathology , Bucladesine/pharmacology , Cell Differentiation/drug effects , Cell Differentiation/genetics , Cell Line, Tumor , Colforsin/pharmacology , Glial Fibrillary Acidic Protein/metabolism , Intracellular Membranes/drug effects , Isoquinolines/pharmacology , Protein Kinase Inhibitors/pharmacology , Protein Transport/drug effects , Rats , Receptors, Notch/drug effects , Receptors, Notch/genetics , Signal Transduction/drug effects , Subcellular Fractions/drug effects , Subcellular Fractions/metabolism , Sulfonamides/pharmacology , Transcriptional Activation/drug effects , Transfection , Up-Regulation/drug effects
13.
PLoS One ; 8(12): e84838, 2013.
Article in English | MEDLINE | ID: mdl-24391977

ABSTRACT

Neural stem and progenitor cells (NSCs/NPCs) are distinct groups of cells found in the mammalian central nervous system (CNS). Previously we determined that members of the High Mobility Group (HMG) B family of chromatin structural proteins modulate NSC proliferation and self-renewal. Among them HMGB2 was found to be dynamically expressed in proliferating and differentiating NSCs, suggesting that it may regulate NSC maintenance. We report now that Hmgb2(-/-) mice exhibit SVZ hyperproliferation, increased numbers of SVZ NSCs, and a trend towards aberrant increases in newly born neurons in the olfactory bulb (OB) granule cell layer. Increases in the levels of the transcription factor p21 and the Neural cell adhesion molecule (NCAM), along with down-regulation of the transcription/pluripotency factor Oct4 in the Hmgb2-/- SVZ point to a possible pathway for this increased proliferation/differentiation. Our findings suggest that HMGB2 functions as a modulator of neurogenesis in young adult mice through regulation of NSC proliferation, and identify a potential target via which CNS repair could be amplified following trauma or disease-based neuronal degeneration.


Subject(s)
Cell Proliferation , HMGB2 Protein/deficiency , Neural Stem Cells/physiology , Neurogenesis/genetics , Animals , Blotting, Western , Cells, Cultured , DNA Primers/genetics , HMGB2 Protein/metabolism , Lateral Ventricles/cytology , Mice , Mice, Inbred C57BL , Mice, Knockout , Microscopy, Fluorescence , Neural Stem Cells/metabolism , Neurogenesis/physiology , Reverse Transcriptase Polymerase Chain Reaction , Statistics, Nonparametric
14.
J Neurosci ; 32(42): 14775-93, 2012 Oct 17.
Article in English | MEDLINE | ID: mdl-23077062

ABSTRACT

Diffuse white matter injury (DWMI) caused by hypoxia is associated with permanent neurodevelopmental disabilities in preterm infants. The cellular and molecular mechanisms producing DWMI are poorly defined. Using a mouse model of neonatal hypoxia, we demonstrate a biphasic effect on oligodendrocyte development, resulting in hypomyelination. Oligodendrocyte death and oligodendrocyte progenitor cell (OPC) proliferation during the week after hypoxia were followed by delayed oligodendrocyte differentiation and abnormal myelination, as demonstrated by electron microscopy. Cdk2 activation was essential for the regenerative OPC response after hypoxia and was accompanied by reduced FoxO1-dependent p27(Kip1) expression. p27(Kip1) was also reduced in OPCs in human infant white matter lesions after hypoxia. The negative effects of hypoxia on oligodendrogenesis and myelination were more pronounced in p27(Kip1)-null mice; conversely, overexpression of FoxO1 or p27(Kip1) in OPCs after hypoxia promoted oligodendrogenesis. Our studies demonstrate for the first time that neonatal hypoxia affects the Foxo1/p27(Kip1) pathway during white matter development. We also show that molecular manipulation of this pathway enhances oligodendrocyte regeneration during a critical developmental time window after DWMI. Thus, FoxO1 and p27(Kip1) may serve as promising target molecules for promoting timely oligodendrogenesis in neonatal DWMI.


Subject(s)
Cell Differentiation/physiology , Cyclin-Dependent Kinase Inhibitor p27/biosynthesis , Forkhead Transcription Factors/physiology , Gene Expression Regulation, Developmental , Hypoxia, Brain/metabolism , Nerve Regeneration/physiology , Oligodendroglia/physiology , Animals , Animals, Newborn , Cells, Cultured , Cyclin-Dependent Kinase Inhibitor p27/genetics , Forkhead Box Protein O1 , Humans , Hypoxia, Brain/pathology , Infant , Infant, Newborn , Mice , Mice, 129 Strain , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Oligodendroglia/cytology
15.
Nature ; 467(7313): 323-7, 2010 Sep 16.
Article in English | MEDLINE | ID: mdl-20844536

ABSTRACT

Specialized cellular microenvironments, or 'niches', modulate stem cell properties, including cell number, self-renewal and fate decisions. In the adult brain, niches that maintain a source of neural stem cells (NSCs) and neural progenitor cells (NPCs) are the subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus of the hippocampus. The size of the NSC population of the SVZ at any time is the result of several ongoing processes, including self-renewal, cell differentiation, and cell death. Maintaining the balance between NSCs and NPCs in the SVZ niche is critical to supply the brain with specific neural populations, both under normal conditions or after injury. A fundamental question relevant to both normal development and to cell-based repair strategies in the central nervous system is how the balance of different NSC and NPC populations is maintained in the niche. EGFR (epidermal growth factor receptor) and Notch signalling pathways have fundamental roles during development of multicellular organisms. In Drosophila and in Caenorhabditis elegans these pathways may have either cooperative or antagonistic functions. In the SVZ, Notch regulates NSC identity and self-renewal, whereas EGFR specifically affects NPC proliferation and migration. This suggests that interplay of these two pathways may maintain the balance between NSC and NPC numbers. Here we show that functional cell-cell interaction between NPCs and NSCs through EGFR and Notch signalling has a crucial role in maintaining the balance between these cell populations in the SVZ. Enhanced EGFR signalling in vivo results in the expansion of the NPC pool, and reduces NSC number and self-renewal. This occurs through a non-cell-autonomous mechanism involving EGFR-mediated regulation of Notch signalling. Our findings define a novel interaction between EGFR and Notch pathways in the adult SVZ, and thus provide a mechanism for NSC and NPC pool maintenance.


Subject(s)
ErbB Receptors/metabolism , Neurons/cytology , Receptors, Notch/metabolism , Signal Transduction , Stem Cells/cytology , Animals , Cell Count , Cell Division , ErbB Receptors/genetics , Humans , Membrane Proteins/deficiency , Membrane Proteins/genetics , Membrane Proteins/metabolism , Mice , Mice, Inbred C57BL , Nerve Tissue Proteins/deficiency , Nerve Tissue Proteins/genetics , Nerve Tissue Proteins/metabolism , Protein Binding , Receptor, Notch1/metabolism , Stem Cell Niche/cytology , Ubiquitination
16.
Nat Neurosci ; 13(5): 541-550, 2010 May.
Article in English | MEDLINE | ID: mdl-20418875

ABSTRACT

The mechanisms that regulate the developmental potential of adult neural progenitor populations under physiological and pathological conditions remain poorly defined. Glutamic acid decarboxylase 65 (GAD65)- and Doublecortin (Dcx)-expressing cells constitute major progenitor populations in the adult mouse subventricular zone (SVZ). Under normal physiological conditions, SVZ-derived GAD65-positive and Dcx-positive cells expressed the transcription factor Pax6 and migrated along the rostral migratory stream to the olfactory bulb to generate interneurons. After lysolecithin-induced demyelination of corpus callosum, however, these cells altered their molecular and cellular properties and migratory path. Demyelination upregulated chordin in the SVZ, which redirected GAD65-positive and Dcx-positive progenitors from neuronal to glial fates, generating new oligodendrocytes in the corpus callosum. Our findings suggest that the lineage plasticity of SVZ progenitor cells could be a potential therapeutic strategy for diseased or injured brain.


Subject(s)
Adult Stem Cells/drug effects , Cell Differentiation/drug effects , Cell Lineage/drug effects , Cerebral Ventricles/pathology , Demyelinating Diseases/pathology , Glycoproteins/pharmacology , Intercellular Signaling Peptides and Proteins/pharmacology , Neurons/drug effects , Animals , Bromodeoxyuridine/metabolism , Cell Count/methods , Cell Differentiation/genetics , Cell Lineage/genetics , Cell Movement/drug effects , Corpus Callosum/cytology , Demyelinating Diseases/chemically induced , Doublecortin Domain Proteins , Doublecortin Protein , Gene Expression Regulation/drug effects , Glutamate Decarboxylase/genetics , Green Fluorescent Proteins/genetics , Lysophosphatidylcholines , Mice , Mice, Transgenic , Microtubule-Associated Proteins/genetics , Myelin Basic Protein/metabolism , Nerve Tissue Proteins/metabolism , Neurogenesis/drug effects , Neurogenesis/genetics , Neuronal Plasticity/drug effects , Neurons/physiology , Neuropeptides/genetics , Oligodendroglia/drug effects , Oligodendroglia/physiology
17.
Nat Neurosci ; 13(3): 287-289, 2010 Mar.
Article in English | MEDLINE | ID: mdl-20173746

ABSTRACT

We found that demyelinated axons formed functional glutamatergic synapses onto adult-born NG2(+) oligodendrocyte progenitor cells (OPCs) migrating from the subventricular zone after focal demyelination of adult mice corpus callosum. This glutamatergic input was substantially reduced compared with endogenous callosal OPCs 1 week after lesion and was lost on differentiation into oligodendrocytes. Therefore, axon-oligodendrocyte progenitor synapse formation is a transient and regulated step that occurs during remyelination of callosal axons.


Subject(s)
Adult Stem Cells/physiology , Corpus Callosum/physiopathology , Myelin Sheath/physiology , Oligodendroglia/physiology , Stem Cell Niche/physiology , Synapses/physiology , Animals , Axons/physiology , Cell Differentiation , Cell Movement , Corpus Callosum/injuries , Excitatory Postsynaptic Potentials , Glutamic Acid/metabolism , In Vitro Techniques , Membrane Potentials/physiology , Mice , Mice, Inbred C57BL , Mice, Transgenic , NIH 3T3 Cells , Neurons/physiology , Synaptic Transmission/physiology
18.
J Neurosci ; 29(32): 10047-62, 2009 Aug 12.
Article in English | MEDLINE | ID: mdl-19675238

ABSTRACT

In the postnatal brain, oligodendrocyte progenitor cells (OPCs) arise from the subventricular zone (SVZ) and migrate into the developing white matter, where they differentiate into oligodendrocytes and myelinate axons. The mechanisms regulating OPC migration and differentiation are not fully defined. The present study demonstrates that endothelin-1 (ET-1) is an astrocyte-derived signal that regulates OPC migration and differentiation. OPCs in vivo and in culture express functional ET(A) and ET(B) receptors, which mediate ET-1-induced ERK (extracellular signal-regulated kinase) and CREB (cAMP response element-binding protein) phosphorylation. ET-1 exerts both chemotactic and chemokinetic effects on OPCs to enhance cell migration; it also prevents lineage progression from the O4(+) to the O1(+) stage without affecting cell proliferation. Astrocyte-conditioned medium stimulates OPC migration in culture through ET receptor activation, whereas multiphoton time-lapse imaging shows that selective ET receptor antagonists or anti-ET-1 antibodies inhibit OPC migration from the SVZ. Inhibition of ET receptor activity also derepresses OPC differentiation in the corpus callosum in slice cultures. Our findings indicate that ET-1 is a soluble astrocyte-derived signal that regulates OPC migration and differentiation during development.


Subject(s)
Endothelin-1/metabolism , Oligodendroglia/physiology , Stem Cells/physiology , Animals , Astrocytes/metabolism , Autoantibodies , Brain/physiology , Cell Differentiation/physiology , Cell Lineage/physiology , Cell Movement/physiology , Cells, Cultured , Chemotaxis/physiology , Culture Media, Conditioned , Cyclic AMP Response Element-Binding Protein/metabolism , Endothelin A Receptor Antagonists , Endothelin B Receptor Antagonists , Endothelin-1/immunology , Extracellular Signal-Regulated MAP Kinases/metabolism , Humans , In Vitro Techniques , Mice , Mice, Transgenic , Rats , Receptor, Endothelin A/metabolism , Receptor, Endothelin B/metabolism , Swine
19.
J Neurosci ; 29(9): 2902-14, 2009 Mar 04.
Article in English | MEDLINE | ID: mdl-19261886

ABSTRACT

Neuronal progenitor cells of the anterior subventricular zone (SVZa) migrate along the rostral migratory stream (RMS) to the olfactory bulb, where they exit the cell cycle and differentiate. The molecular mechanisms that regulate SVZa progenitor proliferation and cell-cycle exit are largely undefined. We investigated the role of p27(KIP1) in regulating cell proliferation and survival in the RMS and olfactory bulb between postnatal day 1 (P1) and P14, the peak period of olfactory bulb neuron generation. A large proportion of cells in the RMS and the olfactory bulb express cytoplasmic p27(KIP1), but a small percentage display high nuclear p27(KIP1) immunostaining, which exhibit a caudal(low)-rostral(high) gradient: lowest in the SVZa and highest in the glomerular layer of the olfactory bulb. p27(KIP1) is also present in the nucleus and/or the cytoplasm of neuron-specific type III beta-tubulin(+) cells. Cells with strong nuclear p27(KIP1) expression are BrdU(-) and Ki67(-). The percentage of BrdU(+) cells in the SVZa, RMS, and olfactory bulb is higher in p27(KIP1) null than wild-type (WT) mice at all ages analyzed. Consistent with these findings, p27(KIP1) overexpression in cultured p27(KIP1) null and WT SVZ cells reduced cell proliferation and self-renewal. Finally, in p27(KIP1) null mice, the diameter of the horizontal limb of the RMS is larger than in WT mice, and development of the olfactory bulb granule cell layer is delayed, together with increased apoptotic cell density. Our results indicate that in the postnatal brain, p27(KIP1) regulates the proliferation and survival of neuronal cells in the RMS and olfactory bulb.


Subject(s)
Animals, Newborn/physiology , Cell Movement/physiology , Cyclin-Dependent Kinase Inhibitor p27/physiology , Olfactory Bulb/physiology , Animals , Antimetabolites , Blotting, Western , Bromodeoxyuridine , CDC2 Protein Kinase/antagonists & inhibitors , Cell Proliferation , Cell Survival , DNA-Binding Proteins , Immunohistochemistry , In Situ Nick-End Labeling , Mesencephalon/cytology , Mesencephalon/growth & development , Mesencephalon/physiology , Mice , Mice, Knockout , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Nuclear Proteins/biosynthesis , Nuclear Proteins/genetics , Olfactory Bulb/cytology , Olfactory Bulb/growth & development
20.
J Cell Biol ; 179(6): 1231-45, 2007 Dec 17.
Article in English | MEDLINE | ID: mdl-18086919

ABSTRACT

We investigated the function of cyclin-dependent kinase 2 (Cdk2) in neural progenitor cells during postnatal development. Chondroitin sulfate proteoglycan (NG2)-expressing progenitor cells of the subventricular zone (SVZ) show no significant difference in density and proliferation between Cdk2(-/-) and wild-type mice at perinatal ages and are reduced only in adult Cdk2(-/-) mice. Adult Cdk2(-/-) SVZ cells in culture display decreased self-renewal capacity and enhanced differentiation. Compensatory mechanisms in perinatal Cdk2(-/-) SVZ cells, which persist until postnatal day 15, involve increased Cdk4 expression that results in retinoblastoma protein inactivation. A subsequent decline in Cdk4 activity to wild-type levels in postnatal day 28 Cdk2(-/-) cells coincides with lower NG2+ proliferation and self-renewal capacity similar to adult levels. Cdk4 silencing in perinatal Cdk2(-/-) SVZ cells abolishes Cdk4 up-regulation and reduces cell proliferation and self- renewal to adult levels. Conversely, Cdk4 overexpression in adult SVZ cells restores proliferative capacity to wild-type levels. Thus, although Cdk2 is functionally redundant in perinatal SVZ, it is important for adult progenitor cell proliferation and self-renewal through age-dependent regulation of Cdk4.


Subject(s)
Cerebral Ventricles/cytology , Cyclin-Dependent Kinase 2/physiology , Neurons/cytology , Stem Cells/cytology , Animals , Cell Cycle Proteins/genetics , Cell Cycle Proteins/metabolism , Cell Lineage , Cell Proliferation , Cerebral Ventricles/metabolism , Chondroitin Sulfate Proteoglycans/metabolism , Cyclin-Dependent Kinase 4/physiology , Gene Expression Regulation, Developmental , Mice , Stem Cells/metabolism
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