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1.
Development ; 151(1)2024 Jan 01.
Article in English | MEDLINE | ID: mdl-38063486

ABSTRACT

Cholinergic signaling plays a crucial role in the regulation of adult hippocampal neurogenesis; however, the mechanisms by which acetylcholine mediates neurogenic effects are not completely understood. Here, we report the expression of muscarinic acetylcholine receptor subtype M4 (M4 mAChR) on a subpopulation of neural precursor cells (NPCs) in the adult mouse hippocampus, and demonstrate that its pharmacological stimulation promotes their proliferation, thereby enhancing the production of new neurons in vivo. Using a targeted ablation approach, we also show that medial septum (MS) and the diagonal band of Broca (DBB) cholinergic neurons support both the survival and morphological maturation of adult-born neurons in the mouse hippocampus. Although the systemic administration of an M4-selective allosteric potentiator fails to fully rescue the MS/DBB cholinergic lesion-induced decrease in hippocampal neurogenesis, it further exacerbates the impairment in the morphological maturation of adult-born neurons. Collectively, these findings reveal stage-specific roles of M4 mAChRs in regulating adult hippocampal neurogenesis, uncoupling their positive role in enhancing the production of new neurons from the M4-induced inhibition of their morphological maturation, at least in the context of cholinergic signaling dysfunction.


Subject(s)
Neural Stem Cells , Receptor, Muscarinic M4 , Mice , Animals , Receptor, Muscarinic M4/metabolism , Neural Stem Cells/metabolism , Hippocampus/metabolism , Neurogenesis/genetics , Cholinergic Agents/metabolism , Cholinergic Agents/pharmacology , Cell Proliferation
2.
Dev Neurobiol ; 79(9-10): 868-879, 2019 09.
Article in English | MEDLINE | ID: mdl-31886631

ABSTRACT

Brain-derived neurotrophic factor (BDNF) signaling plays a major role in the regulation of hippocampal neurogenesis in the adult brain. While the majority of studies suggest that this is due to its effect on the survival and differentiation of newborn neurons, it remains unclear whether this signaling directly regulates neural precursor cell (NPC) activity and which of its two receptors, TrkB or the p75 neurotrophin receptor (p75NTR ) mediates this effect. Here, we examined both the RNA and protein expression of these receptors and found that TrkB but not p75NTR receptors are expressed by hippocampal NPCs in the adult mouse brain. Using a clonal neurosphere assay, we demonstrate that pharmacological blockade of TrkB receptors directly activates a distinct subpopulation of NPCs. Moreover, we show that administration of ANA-12, a TrkB-selective antagonist, in vivo either by systemic intraperitoneal injection or by direct infusion within the hippocampus leads to an increase in the production of new neurons. In contrast, we found that NPC-specific knockout of p75NTR had no effect on the proliferation of NPCs and did not alter neurogenesis in the adult hippocampus. Collectively, these results demonstrate a novel role of TrkB receptors in directly regulating the activity of a subset of hippocampal NPCs and suggest that the transient blockade of these receptors could be used to enhance adult hippocampal neurogenesis.


Subject(s)
Brain/metabolism , Hippocampus/metabolism , Neurogenesis/physiology , Receptor, Nerve Growth Factor/metabolism , Animals , Cell Differentiation/physiology , Cells, Cultured , Female , Male , Mice , Neural Stem Cells/metabolism , Neurons/metabolism , Signal Transduction/physiology
3.
Cancer Med ; 5(4): 649-55, 2016 Apr.
Article in English | MEDLINE | ID: mdl-26773710

ABSTRACT

Cancer is one of the leading causes of death worldwide, and is estimated to be a reason of death of more than 18 billion people in the coming 5 years. Progress has been made in diagnosis and treatment of cancer; however, a sound understanding of the underlying cell biology still remains an unsolved mystery. Current treatments include a combination of radiation, surgery, and/or chemotherapy. However, these treatments are not a complete cure, aimed simply at shrinking the tumor and in majority of cases, there is a relapse of tumor. Several evidences suggest the presence of cancer stem cells (CSCs) or tumor-initiating stem-like cells, a small population of cells present in the tumor, capable of self-renewal and generation of differentiated progeny. The presence of these CSCs can be attributed to the failure of cancer treatments as these cells are believed to exhibit therapy resistance. As a result, increasing attention has been given to CSC research to resolve the therapeutic problems related to cancer. Progress in this field of research has led to the development of novel strategies to treat several malignancies and has become a hot topic of discussion. In this review, we will briefly focus on the main characteristics, therapeutic implications, and perspectives of CSCs in cancer therapy.


Subject(s)
Neoplasms/metabolism , Neoplasms/pathology , Neoplastic Stem Cells/metabolism , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Biomarkers , Gene Expression Regulation, Neoplastic/drug effects , Humans , MicroRNAs/genetics , Molecular Targeted Therapy , Neoplasm Metastasis , Neoplasms/drug therapy , Neoplasms/etiology , Neoplastic Stem Cells/drug effects , Phenotype , Signal Transduction/drug effects
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