Of microtubules and memory: implications for microtubule dynamics in dendrites and spines

Dent, Erik W.

doi:10.1091/mbc.e15-11-0769

Cited by 117 publications

(106 citation statements)

References 82 publications

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“…Microtubules polymerize transiently into spines and regulate their morphology as well as synaptic plasticity through a cytoskeletal cross-talk with actin (55 – 57). Because microtubule invasions seem to specifically target spines that are undergoing activity-dependent changes, one hypothesis is that this process helps to regulate synaptic plasticity through molecular cargo transport to the synapse (58, 59). Overall, Dcx many interactions with the cytoskeleton are likely to contribute to its regulation of dendritic development, spine morphology and synaptogenesis.…”

Section: Discussionmentioning

confidence: 99%

Correct laminar positioning in the neocortex influences proper dendritic and synaptic development

Martineau

Sahu

Plantier

et al. 2017

Preprint

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18The neocortex is a six-layered laminated structure with a precise anatomical and functional 19 organization ensuring proper function. Laminar positioning of cortical neurons, as determined by 20 termination of neuronal migration, is a key determinant of their ability to assemble into functional 21 circuits. However, the exact contribution of laminar placement to dendrite morphogenesis and 22 synapse formation remains unclear. Here we manipulated the laminar position of cortical neurons by 23 knocking down Dcx, a crucial effector of migration, and show that misplaced neurons fail to properly 24 form dendrites, spines and functional glutamatergic synapses. We further show that knocking down 25

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Section: Discussionmentioning

confidence: 99%

Correct laminar positioning in the neocortex influences proper dendritic and synaptic development

Martineau

Sahu

Plantier

et al. 2017

Preprint

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“…Microtubule-associated protein 2 (MAP2); microtubule dynamics have been shown to influence dendritic spine morphology 42,43 and 3) We have previously reported altered morphology of pyramidal neurons in the aCC of female Brd1 +/mice 14 . We hypothesized here that dendritic spine morphology in addition is altered in Brd1 +/mouse brain, and performed a morphology analysis of dendritic spines derived from aCC pyramidal neurons.…”

Section: Brd1 Deficiency Is Associated With Changes In Dendritic Spinmentioning

confidence: 99%

Brain proteome changes in female Brd1 mice unmask dendritic spine pathology and show enrichment for schizophrenia risk

Paternoster

Svanborg

Edhager

et al. 2019

Neurobiology of Disease

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2018). Brain proteome changes in female Brd1 +/ mice unmask dendritic spine pathology and show enrichment for schizophrenia risk. Neurobiology of Disease. https://doi.Brain proteome changes in female Brd1+/− mice unmask dendritic spine pathology and show enrichment for schizophrenia risk. Ynbdi (2018), https://doi. AbstractGenetic and molecular studies have implicated the Bromodomain containing 1 (BRD1) gene in the pathogenesis of schizophrenia and bipolar disorder. Accordingly, mice heterozygous for a targeted deletion of Brd1 (Brd1 +/mice) show behavioral phenotypes with broad translational relevance to psychiatric disorders. BRD1 encodes a scaffold protein that affects the expression of many genes through modulation of histone acetylation. BRD1 target genes have been identified in cell lines; however the impact of reduced Brd1 levels on the brain proteome is largely unknown. In this study, we applied labelbased quantitative mass spectrometry to profile the frontal cortex, hippocampus and striatum proteome and synaptosomal proteome of female Brd1 +/mice. We successfully quantified between 1537 and 2196 proteins and show widespread changes in protein abundancies and compartmentalization. By integrative analysis of human genetic data, we find that the differentially abundant proteins in frontal cortex and hippocampus are enriched for schizophrenia risk further linking the actions of BRD1 to psychiatric disorders. Affected proteins were further enriched for proteins involved in processes known to influence neuronal and dendritic spine morphology e.g. regulation of cytoskeleton dynamics and mitochondrial function. Directly prompted in these findings, we investigated dendritic spine morphology of pyramidal neurons in anterior cingulate cortex and found them significantly altered, including reduced size of small dendritic spines and decreased number of the mature mushroom type. Collectively, our study describes known as well as new mechanisms related to BRD1 dysfunction and its role in psychiatric disorders, and provides evidence for the molecular and cellular dysfunctions underlying altered neurosignalling and cognition in Brd1 +/mice.

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“…Cell adhesion is an important process in human-specific cortical folding and apical progenitors cell cycle [Mora-Bermúdez et al, 2016, Wianny et al, 2018]. Microtubule dynamics play an important role in neurodegenerative diseases such as Alzheimer’s [Hernández et al, 2013] but also in learning and memory [Dent, 2017].…”

Section: Resultsmentioning

confidence: 99%

“…Our data also shows that genes affected by eQTLs are enriched in the regulation of microtubule dynamics. Microtubule depolymerization plays a crucial role in neuronal development and synaptic plasticity [Dent, 2017], as well as in the pathogenesis of Alzheimer’s Disease [Hernández et al, 2013]. Among the genes affecting microtubule dynamics we found one that is associated to a cellular phenotype in the same tissue where the human eQTL is affecting expression levels: FMN1 in the hippocampus.…”

Section: Discussionmentioning

confidence: 99%

Modern human alleles differentially regulate gene expression across brain regions: implications for brain evolution

Andirkó

Boeckx

2019

Preprint

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8The high-quality sequence of the genomes of our extinct relatives, Ne-9 anderthals and Denisovans, became recently public. At the same time, 10 we have seen the emergence of big databases of modern human genetic 11 variation. However, linking human genetic variation, neuronal phenotypes 12 and, eventually, behaviour, is only possible if we understand how variation 13 and genetic regulation interact. We used two publicly available datasets, 14 the GTEX cis-eQTL database (v7) and a catalog of high-frequency Homo 15 Sapiens specific alleles relative to the Neanderthals and Denisovan se-16 quences, to understand how high-frequency Homo Sapiens derived alleles 17 affect gene expression regulation. The resulting dataset shows that genes 18 associated with brain development are affected by Homo sapiens-specific 19 eQTL in brain areas key in human evolution such as the cerebellum. We 20 also show that some of these eQTL overlap significantly with putative 21 regions of positive selection relative to archaic humans [Peyrégne et al., 22 2017]. Additionally, we tested whether any of the variants are associated 23 with clinical conditions in modern human populations. These findings can 24 inform future experimental work and enrich current venues of research of 25 the Homo Sapiens brain evolution, such as the relationship between clini-26 cal and evolutionary research and the recent expansion of the cerebellum 27 in Homo Sapiens [Gunz et al., 2010].28 Keywords-Human evolution, eQTL, brain evolution 29 and Boeckx, 2019]). 75 Our results show differential regulation by derived cis-eQTLs in key brain 76 areas and circuits that are claimed to have changed significantly during the 77 emergence of Homo sapiens, such as the cerebellum and olfactory signalling 78 pathway [Bastir et al., 2011]. We also found genetic regulation of cellular pro-79 cesses that can potentially impact neurodevelopment and disease, such as fo-80 late one-carbon metabolism, aerobic glycolysis regulation, cell-cell adhesion and 81 regulation of cytoskeleton dynamics. Some of these processes, such as aerobic 82 glycolysis, have already been discussed in other studies in the context of human 83 evolution and human-specific diseases such as Alzheimer's Disease [Bufill et al., 84 2011]. While we limited the scope of our study to brain tissue, we found as 85 well eQTLs associated with neural crest cell development and the craniofacial 86 complex. This is of special interest, as the Homo sapiens face has a distinct re-87 tracted profile compared to that of archaic humans [Lacruz et al., 2019]. Some 88 of the genes that affect brain development might exert an influence in adjacent 89 tissues [Boeckx, 2017]. 90 Since the eQTLs affect genes previously identified as under selective sweep in 91 modern humans relative to archaic humans, we tested whether the eQTLs affect 92 128 2015]. In this case, the effect of an eQTL is understood as the relative gene 129 expression difference between the minor, ancestral allele and the high-frequency 130 derived allele. As shown ...

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Of microtubules and memory: implications for microtubule dynamics in dendrites and spines

Cited by 117 publications

References 82 publications

Correct laminar positioning in the neocortex influences proper dendritic and synaptic development

Correct laminar positioning in the neocortex influences proper dendritic and synaptic development

Brain proteome changes in female Brd1 mice unmask dendritic spine pathology and show enrichment for schizophrenia risk

Modern human alleles differentially regulate gene expression across brain regions: implications for brain evolution

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