Dataset Information

Astrocytes modulate neuronal development by S100A6 signaling

ABSTRACT: Neuronal morphogenesis relies on intercellular signaling. Astrocytes release metabolites, trophic, and guidance factors to promote neuronal maturation. In contrast, the mechanisms by which astrocytes could limit and stabilize neuronal connectivity remain less explored. Here, we find cortical astrocytes to express and release S100A6, a Ca2+-binding protein (‘calcyclin’). Simultaneously, the majority of cortical neurons expressed calcyclin-binding protein (CaCyBp), a bona fide binding partner for S100A6. In neurons, CaCyBp maintained the unfolded protein response pathway, thereby controlling proteostasis. When released, S100A6 inhibited CaCyBp-mediated signaling, thus slowing protein turnover, and, consequently, neuritogenesis. S100A6-CaCyBp signaling during gestation was sensitive to the mother’s nu tritional status, particularly eicosapentaenoic acid intake. Thus, a member of the S100 protein family acts as an astroglia-derived morphogen, whose action on neurons is modulated by environmental factors.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Brain

SUBMITTER: Sally Shirran

LAB HEAD: Tibor Harkany

PROVIDER: PXD066923 | Pride | 2025-09-11

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	CDJun_iTRAQFr10half.wiff	Wiff
	CDJun_iTRAQFr10half.wiff.scan	Wiff
	DCJun_iTRAQ2Fr11half.wiff	Wiff
	DCJun_iTRAQ2Fr11half.wiff.scan	Wiff
	DCJun_iTRAQ2Fr12half.wiff	Wiff

Items per page:

1 - 5 of 30

Similar Datasets

Project description:The evolution of human diets led to preferences towards polyunsaturated fatty acid (PUFA) content with ‘Western’ diets enriched in w-6 PUFA1. Mounting evidence points to w-6 PUFA excess limiting metabolic and cognitive processes that define longevity in humans2. When chosen during pregnancy, w-6 PUFA-enriched ‘Western’ diets can reprogram maternal bodily metabolism with maternal nutrient supply precipitating the body-wide imprinting of molecular and cellular adaptations at the level of long-range intercellular signaling networks in the unborn fetus2,3. Even though unfavorable neurological outcomes are amongst the most common complications of intrauterine w-6 PUFA excess3, cellular underpinnings of life-long modifications to brain architecture remain unknown. Here, we show that nutritional w-6 PUFA-derived endocannabinoids desensitize CB1 cannabinoid receptors, thus inducing epigenetic repression of transcriptional regulatory networks controlling neuronal differentiation. We found that cortical neurons lose their positional identity and axonal selectivity once exposing mouse fetuses to excess w-6 PUFAs in utero. Conversion of w-6 PUFAs into endocannabinoids disrupted the temporal precision of signaling at neuronal CB1 cannabinoid receptors, chiefly deregulating Stat3-dependent transcriptional cascades otherwise required to execute neuronal differentiation programs. Global proteomics identified the immunoglobulin family of cell adhesion molecules (IgCAMs) as direct substrates with DNA methylome analysis and ATAC-seq uncovering epigenetic reprogramming at >1,400 sites in neurons after prolonged cannabinoid exposure. We find anxiety and depression-like behavioral traits to manifest in adult offspring, which is compatible with genetic models of reduced IgCAM expression to suggest causality to cortical wiring defects4. Overall, our data uncover a regulatory mechanism whose disruption by maternal food choices could limit the offsprings’ brain function for life.

Project description:Toxoplasma gondii (T. gondii) cyst formation in the central nervous system only occurs in neurons allowing the parasite to remain latent for the lifetime of the host. Astrocytes are fundamental to neuronal health by providing nutrients and structural support and help regulate neurotransmitters by continuous communication with neurons. It is not yet known how infection and the presence of intracellular cysts, disrupts the crucial relationship between these cells. Extracellular vesicles (EVs) function in intracellular communication and can contain proteins, lipids, DNA, miRNA, and other RNA subtypes. EVs are produced by all cells including neurons and play an important role in neuronal-astrocyte interactions including the regulation of glutamate receptors on astrocytes. Previous work has demonstrated Toxoplasma infection reduces astrocytic expression of the primary glutamate transporter, GLT-1. Here we tested if cyst infection of neurons alters the production and content of EVs. EVs were isolated from uninfected and infected primary murine cortical neurons and their size, concentration, and characterization were confirmed with nanoparticle tracking analysis (NTA), transmission electron microscopy (TEM), CD63 ELISA, liquid chromatography (LC)-mass spectrometry (MS)/MS, and microRNA Sequencing. Analysis reveals that infection of neurons reduced neuronal production of EVs and altered their protein and miRNA content. EVs from infected neurons contained secreted Toxoplasma proteins GRA1, GRA2, GRA7, MAG1 and MAG2 associated with cyst formation. Following incubation of neuronal EVs with primary astrocytes, a proportion of EVs colocalize to the nucleus. EVs from infected neurons altered gene expression of astrocytes leading to a downregulation of GLT-1 protein expression and an increase in pro-inflammatory transcriptional signatures. These results demonstrate the ability of a parasitic infection in the brain to alter EV production and the fundamental communication between neurons and astrocytes.

Dataset Information

Astrocytes modulate neuronal development by S100A6 signaling

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets