Increased Sociability in Mice Lacking Intergenic Dlx Enhancers

Darbandi, Siavash Fazel; Esau, Crystal; Lesage-Pelletier, Cindy; Monis, Simon; Poitras, Luc; Yu, Man; Perin, Sofia; Hatch, Gary; Ekker, Marc

doi:10.3389/fnins.2021.718948

Cited by 7 publications

(3 citation statements)

References 33 publications

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“…In addition, we observed a similar pattern of downregulation for glutamate decarboxylase 1 (GAD1), a GABAergic marker that is regulated by the DLX TFs [68,69] (Fig. 5J).…”

Section: Hd Alters the Neurodevelopmental Program Of Msnssupporting

confidence: 52%

Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington’s Disease and Possible Therapeutic Avenues

Aquirre

Tshilenge

Battistoni

et al. 2023

Preprint

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Huntington's disease (HD) is a neurodegenerative disorder caused by an expansion of CAG repeats in exon 1 of the HTT gene, ultimately resulting in the generation of a mutant HTT (mHTT) protein. Although mHTT is expressed in various tissues, it significantly affects medium spiny neurons (MSNs) in the striatum, resulting in their loss and subsequent motor function impairment in HD. While HD symptoms typically emerge in midlife, disrupted MSN neurodevelopment has an important role. To explore the effects of mHTT on MSN development, we differentiated HD induced pluripotent stem cells (iPSC) and isogenic controls into neuronal stem cells, and then generated a developing MSN population encompassing early, intermediate progenitors, and mature MSNs. Single-cell RNA sequencing revealed that the developmental trajectory of MSNs in our model closely emulated the trajectory of fetal striatal neurons. However, in the HD MSN cultures, the differentiation process downregulated several crucial genes required for proper MSN maturation, including Achaete-scute homolog 1 and members of the DLX family of transcription factors. Our analysis also uncovered a progressive dysregulation of multiple HD-related pathways as the MSNs matured, including the NRF2-mediated oxidative stress response and mitogen-activated protein kinase signaling. Using the transcriptional profile of developing HD MSNs, we searched the L1000 dataset for small molecules that induce the opposite gene expression pattern. Our analysis pinpointed numerous small molecules with known benefits in HD models, as well as previously untested novel molecules. A top novel candidate, Cerulenin, partially restored the DARPP-32 levels and electrical activity in HD MSNs, and also modulated genes involved in multiple HD-related pathways.

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“…In addition, we observed a similar pattern of downregulation for glutamate decarboxylase 1 (GAD1), a GABAergic marker that is regulated by the DLX TFs [68,69] (Fig. 5J).…”

Section: Hd Alters the Neurodevelopmental Program Of Msnssupporting

confidence: 52%

Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington’s Disease and Possible Therapeutic Avenues

Aquirre

Tshilenge

Battistoni

et al. 2023

Preprint

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show abstract

“…Mice with heterozygous Chd8 mutations exhibit prolonged social interaction duration in tests [ 63 ]. Mice lacking intergenic Dlx enhancers also show increased social interaction [ 64 ]. These reports suggest that the increased duration of interaction in the social interaction test is a social behavior impairment.…”

Section: Discussionmentioning

confidence: 99%

Maternal immunoglobulin G affects brain development of mouse offspring

Sadakata,

Fujii,

Kaneko

et al. 2024

J Neuroinflammation

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Maternal immunoglobulin (Ig)G is present in breast milk and has been shown to contribute to the development of the immune system in infants. In contrast, maternal IgG has no known effect on early childhood brain development. We found maternal IgG immunoreactivity in microglia, which are resident macrophages of the central nervous system of the pup brain, peaking at postnatal one week. Strong IgG immunoreactivity was observed in microglia in the corpus callosum and cerebellar white matter. IgG stimulation of primary cultured microglia activated the type I interferon feedback loop by Syk. Analysis of neonatal Fc receptor knockout (FcRn KO) mice that could not take up IgG from their mothers revealed abnormalities in the proliferation and/or survival of microglia, oligodendrocytes, and some types of interneurons. Moreover, FcRn KO mice also exhibited abnormalities in social behavior and lower locomotor activity in their home cages. Thus, changes in the mother-derived IgG levels affect brain development in offsprings.

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“…Loss of the I56i intergenic enhancer alters the level of expression of Dlx5/6 and results in a decrease in GABAergic cells in the developing forebrain; these mutants demonstrate increased sociability and learning deficits [ 28 , 34 ]. Mutations involving brain Dlx5/6 regulatory regions are, therefore, associated with cognitive abnormalities both in humans and mice.…”

Section: Introductionmentioning

confidence: 99%

Dlx5/6 Expression Levels in Mouse GABAergic Neurons Regulate Adult Parvalbumin Neuronal Density and Anxiety/Compulsive Behaviours

Aouci

Soudany

Maakoul

et al. 2022

Cells

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Neuronal circuits integrating Parvalbumin-positive GABAergic inhibitory interneurons (PV) are essential for normal brain function and are often altered in psychiatric conditions. During development, Dlx5 and Dlx6 (Dlx5/6) genes are involved in the differentiation of PV-interneurons. In the adult, Dlx5/6 continue to be expressed at low levels in most telencephalic GABAergic neurons, but their importance in determining the number and distribution of adult PV-interneurons is unknown. Previously, we have shown that targeted deletion of Dlx5/6 in mouse GABAergic neurons (Dlx5/6VgatCre mice) results in altered behavioural and metabolic profiles. Here we evaluate the consequences of targeted Dlx5/6 gene dosage alterations in adult GABAergic neurons. We compare the effects on normal brain of homozygous and heterozygous (Dlx5/6VgatCre and Dlx5/6VgatCre/+ mice) Dlx5/6 deletions to those of Dlx5 targeted overexpression (GABAergicDlx5/+ mice). We find a linear correlation between Dlx5/6 allelic dosage and the density of PV-positive neurons in the adult prelimbic cortex and in the hippocampus. In parallel, we observe that Dlx5/6 expression levels in GABAergic neurons are also linearly associated with the intensity of anxiety and compulsivity-like behaviours. Our findings reinforce the notion that regulation of Dlx5/6 expression is involved in individual cognitive variability and, possibly, in the genesis of certain neuropsychiatric conditions.

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Increased Sociability in Mice Lacking Intergenic Dlx Enhancers

Cited by 7 publications

References 33 publications

Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington’s Disease and Possible Therapeutic Avenues

Transcriptomic Characterization Reveals Disrupted Medium Spiny Neuron Trajectories in Huntington’s Disease and Possible Therapeutic Avenues

Maternal immunoglobulin G affects brain development of mouse offspring

Dlx5/6 Expression Levels in Mouse GABAergic Neurons Regulate Adult Parvalbumin Neuronal Density and Anxiety/Compulsive Behaviours

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