Integrated transcriptional analysis unveils the dynamics of cellular differentiation in the developing mouse hippocampus

Iacono, Giovanni; Benevento, Marco; Dubos, Aline; Hérault, Yann; Bokhoven, Hans van; Kasri, Nael Nadif; Stunnenberg, Hendrik G.

doi:10.1038/s41598-017-18287-w

Cited by 8 publications

(9 citation statements)

References 32 publications

(41 reference statements)

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“…To unravel the potential molecular mechanisms underlying the learning defects of Dyrk1a C/C mice, we performed genome-wide transcriptional profiling (RNA-seq) of Dyrk1a C/C and control mice in the hippocampus at postnatal day 30, as the brain is fully developed and mature at this stage. Analysis of the RNA-seq exon reads was performed using hypergeometric test and Bonferroni correction (DEseq algorithm, P<0.025) as previously published [ 38 , 47 , 48 ] and identified 297 up-regulated and 257 down-regulated genes in Dyrk1a C/C compared with controls ( S1 Table ). To determine the putative cell types associated with the deregulated genes, we compared the sets of up- and down-regulated genes with the markers of hippocampal cell types obtained from single cell RNA-seq (see Materials and Methods ).…”

Section: Resultsmentioning

confidence: 99%

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

et al. 2021

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Perturbation of the excitation/inhibition (E/I) balance leads to neurodevelopmental diseases including to autism spectrum disorders, intellectual disability, and epilepsy. Loss-of-function mutations in the DYRK1A gene, located on human chromosome 21 (Hsa21,) lead to an intellectual disability syndrome associated with microcephaly, epilepsy, and autistic troubles. Overexpression of DYRK1A, on the other hand, has been linked with learning and memory defects observed in people with Down syndrome (DS). Dyrk1a is expressed in both glutamatergic and GABAergic neurons, but its impact on each neuronal population has not yet been elucidated. Here we investigated the impact of Dyrk1a gene copy number variation in glutamatergic neurons using a conditional knockout allele of Dyrk1a crossed with the Tg(Camk2-Cre)4Gsc transgenic mouse. We explored this genetic modification in homozygotes, heterozygotes and combined with the Dp(16Lipi-Zbtb21)1Yey trisomic mouse model to unravel the consequence of Dyrk1a dosage from 0 to 3, to understand its role in normal physiology, and in MRD7 and DS. Overall, Dyrk1a dosage in postnatal glutamatergic neurons did not impact locomotor activity, working memory or epileptic susceptibility, but revealed that Dyrk1a is involved in long-term explicit memory. Molecular analyses pointed at a deregulation of transcriptional activity through immediate early genes and a role of DYRK1A at the glutamatergic post-synapse by deregulating and interacting with key post-synaptic proteins implicated in mechanism leading to long-term enhanced synaptic plasticity. Altogether, our work gives important information to understand the action of DYRK1A inhibitors and have a better therapeutic approach.

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Section: Resultsmentioning

confidence: 99%

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

et al. 2021

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“…Another plausible hypothesis is that the excessive H3K9 methylation detected at postnatal stages occurred at earlier development stages and is subsequently maintained. Specifically, haploinsufficiency of Ehmt1 could cause aberrant activity of other HMTs such as Suv39H1/2 or SetDB1/2 in the dividing radial glia and/or neuronal progenitors, which are abundant in embryonic stage ( 38 ). Next, the replication machinery would maintain the aberrant H3K9 methylation up to the post-mitotic cells of the postnatal brain ( 39 ).…”

Section: Discussionmentioning

confidence: 99%

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome

Iacono

Dubos

Méziane

et al. 2018

Nucleic Acids Research

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Kleefstra syndrome, a disease with intellectual disability, autism spectrum disorders and other developmental defects is caused in humans by haploinsufficiency of EHMT1. Although EHMT1 and its paralog EHMT2 were shown to be histone methyltransferases responsible for deposition of the di-methylated H3K9 (H3K9me2), the exact nature of epigenetic dysfunctions in Kleefstra syndrome remains unknown. Here, we found that the epigenome of Ehmt1+/− adult mouse brain displays a marked increase of H3K9me2/3 which correlates with impaired expression of protocadherins, master regulators of neuronal diversity. Increased H3K9me3 was present already at birth, indicating that aberrant methylation patterns are established during embryogenesis. Interestingly, we found that Ehmt2+/− mice do not present neither the marked increase of H3K9me2/3 nor the cognitive deficits found in Ehmt1+/− mice, indicating an evolutionary diversification of functions. Our finding of increased H3K9me3 in Ehmt1+/− mice is the first one supporting the notion that EHMT1 can quench the deposition of tri-methylation by other Histone methyltransferases, ultimately leading to impaired neurocognitive functioning. Our insights into the epigenetic pathophysiology of Kleefstra syndrome may offer guidance for future developments of therapeutic strategies for this disease.

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“…We consider developmental transitions as the emergence of “plateaus” in the expression of multiple genes in single structures. We identified such plateaus in RNA expression from RNA sequencing data of bulk from the hippocampus in both species ( Iacono et al, 2017 ). We identified when expressed genes reach a plateau in their expression across 14,417 orthologous genes as defined by the mouse genome database ( Smith et al, 2018 ).…”

Section: Methodsmentioning

confidence: 99%

“…We used normalized RNA sequencing expression made available by the Allen brain Institute. RNA expression from mice hippocampi was obtained from Iacono et al (2017) (GEO: GSE79380). We selected only those models with p -values of coefficients less than 0.05 in humans and mice.…”

Section: Methodsmentioning

confidence: 99%

“…Readers are directed to the early work of Passingham (1985) , and Garwicz et al (2009) , who use similar methods to examine early independent ambulation, as well as that of Halley’s studies of the growth of initial primordia and brain across a wide range of mammals ( Halley, 2016 , 2017 ). More recently, the advent of single cell RNA sequencing provides an exciting opportunity to investigate developmental trajectories of neural subpopulations across species ( Habib et al, 2017 ; Iacono et al, 2017 ; Fan et al, 2018 ; Zhong et al, 2018 ). We here broaden the maturational range of neurodevelopmental ages of studies in our database to capture late stages of hippocampal neurogenesis across species.…”

Section: Introductionmentioning

confidence: 99%

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Comparing Adult Hippocampal Neurogenesis Across Species: Translating Time to Predict the Tempo in Humans

Charvet

Finlay

2018

Front. Neurosci.

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Comparison of neurodevelopmental sequences between species whose initial period of brain organization may vary from 100 days to 1,000 days, and whose progress is intrinsically non-linear presents large challenges in normalization. Comparing adult timelines when lifespans stretch from 1 year to 75 years, when underlying cellular mechanisms under scrutiny do not scale similarly, presents challenges to simple detection and comparison. The question of adult hippocampal neurogenesis has generated numerous controversies regarding its simple presence or absence in humans versus rodents, whether it is best described as the tail of a distribution centered on early neural development, or is several distinct processes. In addition, adult neurogenesis may have substantially changed in evolutionary time in different taxonomic groups. Here, we extend and adapt a model of the cross-species transformation of early neurodevelopmental events which presently reaches up to the equivalent of the third human postnatal year for 18 mammalian species (www.translatingtime.net) to address questions relevant to hippocampal neurogenesis, which permit extending the database to adolescence or perhaps to the whole lifespan. We acquired quantitative data delimiting the envelope of hippocampal neurogenesis from cell cycle markers (i.e., Ki67 and DCX) and RNA sequencing data for two primates (macaque and humans) and two rodents (rat and mouse). To improve species coverage in primates, we gathered the same data from marmosets (Callithrix jacchus), but additionally gathered data on a number of developmental milestones to find equivalent developmental time points between marmosets and other species. When all species are so modeled, and represented in a common time frame, the envelopes of hippocampal neurogenesis are essentially superimposable. Early developmental events involving the olfactory and limbic system start and conclude possibly slightly early in primates than rodents, and we find a comparable early conclusion of primate hippocampal neurogenesis (as assessed by the relative number of Ki67 cells) suggesting a plateau to low levels at approximately 2 years of age in humans. Marmosets show equivalent patterns within neurodevelopment, but unlike macaque and humans may have wholesale delay in the initiation of neurodevelopment processes previously observed in some precocial mammals such as the guinea pig and multiple large ungulates.

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Integrated transcriptional analysis unveils the dynamics of cellular differentiation in the developing mouse hippocampus

Cited by 8 publications

References 32 publications

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

Dyrk1a gene dosage in glutamatergic neurons has key effects in cognitive deficits observed in mouse models of MRD7 and Down syndrome

Increased H3K9 methylation and impaired expression of Protocadherins are associated with the cognitive dysfunctions of the Kleefstra syndrome

Comparing Adult Hippocampal Neurogenesis Across Species: Translating Time to Predict the Tempo in Humans

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