Browsing by Author "Guerra, Miguel V."

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    H3K9 Methyltransferases Suv39h1 and Suv39h2 Control the Differentiation of Neural Progenitor Cells in the Adult Hippocampus
    (2022) Guerra, Miguel V.; Caceres, Matias I.; Herrera-Soto, Andrea; Arredondo, Sebastian B.; Varas-Godoy, Manuel; van Zundert, Brigitte; Varela-Nallar, Lorena
    In the dentate gyrus of the adult hippocampus new neurons are generated from neural precursor cells through different stages including proliferation and differentiation of neural progenitor cells and maturation of newborn neurons. These stages are controlled by the expression of specific transcription factors and epigenetic mechanisms, which together orchestrate the progression of the neurogenic process. However, little is known about the involvement of histone posttranslational modifications, a crucial epigenetic mechanism in embryonic neurogenesis that regulates fate commitment and neuronal differentiation. During embryonic development, the repressive modification trimethylation of histone H3 on lysine 9 (H3K9me3) contributes to the cellular identity of different cell-types. However, the role of this modification and its H3K9 methyltransferases has not been elucidated in adult hippocampal neurogenesis. We determined that during the stages of neurogenesis in the adult mouse dentate gyrus and in cultured adult hippocampal progenitors (AHPs), there was a dynamic change in the expression and distribution of H3K9me3, being enriched at early stages of the neurogenic process. A similar pattern was observed in the hippocampus for the dimethylation of histone H3 on lysine 9 (H3K9me2), another repressive modification. Among H3K9 methyltransferases, the enzymes Suv39h1 and Suv39h2 exhibited high levels of expression at early stages of neurogenesis and their expression decreased upon differentiation. Pharmacological inhibition of these enzymes by chaetocin in AHPs reduced H3K9me3 and concomitantly decreased neuronal differentiation while increasing proliferation. Moreover, Suv39h1 and Suv39h2 knockdown in newborn cells of the adult mouse dentate gyrus by retrovirus-mediated RNA interference impaired neuronal differentiation of progenitor cells. Our results indicate that H3K9me3 and H3K9 methyltransferases Suv39h1 and Suv39h2 are critically involved in the regulation of adult hippocampal neurogenesis by controlling the differentiation of neural progenitor cells.
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    The Rab11-regulated endocytic pathway and BDNF/TrkB signaling: Roles in plasticity changes and neurodegenerative diseases
    (2022) Moya-Alvarado, Guillermo; Guerra, Miguel V.; Tiburcio, Reynaldo; Bravo, Evelyn; Bronfman, Francisca C.
    Neurons are highly polarized cells that rely on the intracellular transport of organelles. This process is regulated by molecular motors such as dynein and kinesins and the Rab family of monomeric GTPases that together help move cargo along microtubules in dendrites, somas, and axons. Rab5-Rab11 GTPases regulate receptor trafficking along early-recycling endosomes, which is a process that determines the intracellular signaling output of different signaling pathways, including those triggered by BDNF binding to its tyrosine kinase receptor TrkB. BDNF is a well-recognized neurotrophic factor that regulates experience-dependent plasticity in different circuits in the brain. The internalization of the BDNF/TrkB complex results in signaling endosomes that allow local signaling in dendrites and presynaptic terminals, nuclear signaling in somas and dynein-mediated long-distance signaling from axons to cell bodies. In this review, we briefly discuss the organization of the endocytic pathway and how Rab11-recycling endosomes interact with other endomembrane systems. We further expand upon the roles of the Rab11-recycling pathway in neuronal plasticity. Then, we discuss the BDNF/TrkB signaling pathways and their functional relationships with the postendocytic trafficking of BDNF, including axonal transport, emphasizing the role of BDNF signaling endosomes, particularly Rab5-Rab11 endosomes, in neuronal plasticity. Finally, we discuss the evidence indicating that the dysfunction of the early-recycling pathway impairs BDNF signaling, contributing to several neurodegenerative diseases.
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    Widespread loss of the silencing epigenetic mark H3K9me3 in astrocytes and neurons along with hippocampal-dependent cognitive impairment in C9orf72 BAC transgenic mice.
    (2020) Jury, Nur.; Abarzúa, Sebastián.; Díaz, Iván; Ampuero, Estibaliz.; Cubillos, Paula.; Martínez, Pablo.; Arredondo Ramírez, Cristian Andrés; Rojas, Fabiola.; Zundert, Brigitte van.; Guerra, Miguel V.
    Abstract Background Hexanucleotide repeat expansions of the G4C2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). Results Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI- or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. Conclusions Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD.Abstract Background Hexanucleotide repeat expansions of the G4C2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). Results Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI- or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. Conclusions Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD.Abstract Background Hexanucleotide repeat expansions of the G4C2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). Results Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI- or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. Conclusions Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD.Abstract Background Hexanucleotide repeat expansions of the G4C2 motif in a non-coding region of the C9ORF72 gene are the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Tissues from C9ALS/FTD patients and from mouse models of ALS show RNA foci, dipeptide-repeat proteins, and notably, widespread alterations in the transcriptome. Epigenetic processes regulate gene expression without changing DNA sequences and therefore could account for the altered transcriptome profiles in C9ALS/FTD; here, we explore whether the critical repressive marks H3K9me2 and H3K9me3 are altered in a recently developed C9ALS/FTD BAC mouse model (C9BAC). Results Chromocenters that constitute pericentric constitutive heterochromatin were visualized as DAPI- or Nucblue-dense foci in nuclei. Cultured C9BAC astrocytes exhibited a reduced staining signal for H3K9me3 (but not for H3K9me2) at chromocenters that was accompanied by a marked decline in the global nuclear level of this mark. Similar depletion of H3K9me3 at chromocenters was detected in astrocytes and neurons of the spinal cord, motor cortex, and hippocampus of C9BAC mice. The alterations of H3K9me3 in the hippocampus of C9BAC mice led us to identify previously undetected neuronal loss in CA1, CA3, and dentate gyrus, as well as hippocampal-dependent cognitive deficits. Conclusions Our data indicate that a loss of the repressive mark H3K9me3 in astrocytes and neurons in the central nervous system of C9BAC mice represents a signature during neurodegeneration and memory deficit of C9ALS/FTD.