Role of Satb1 and Satb2 Transcription Factors in the Glutamate Receptors Expression and Ca2+ Signaling in the Cortical Neurons In Vitro.

Egor A Turovsky,Evgeniya I Fedotova,Maria V Turovskaya,Victor S Tarabykin,Alexey A Babaev,Elena G Varlamova

doi:10.3390/ijms22115968

Abstract

Transcription factors Satb1 and Satb2 are involved in the processes of cortex development and maturation of neurons. Alterations in the expression of their target genes can lead to neurodegenerative processes. Molecular and cellular mechanisms of regulation of neurotransmission by these transcription factors remain poorly understood. In this study, we have shown that transcription factors Satb1 and Satb2 participate in the regulation of genes encoding the NMDA-, AMPA-, and KA- receptor subunits and the inhibitory GABA(A) receptor. Deletion of gene for either Satb1 or Satb2 homologous factors induces the expression of genes encoding the NMDA receptor subunits, thereby leading to higher amplitudes of Ca2+-signals in neurons derived from the Satb1-deficient (Satb1fl/+ * NexCre/+) and Satb1-null mice (Satb1fl/fl * NexCre/+) in response to the selective agonist reducing the EC50 for the NMDA receptor. Simultaneously, there is an increase in the expression of the Gria2 gene, encoding the AMPA receptor subunit, thus decreasing the Ca2+-signals of neurons in response to the treatment with a selective agonist (5-Fluorowillardiine (FW)). The Satb1 deletion increases the sensitivity of the KA receptor to the agonist (domoic acid), in the cortical neurons of the Satb1-deficient mice but decreases it in the Satb1-null mice. At the same time, the Satb2 deletion decreases Ca2+-signals and the sensitivity of the KA receptor to the agonist in neurons from the Satb1-null and the Satb1-deficient mice. The Satb1 deletion affects the development of the inhibitory system of neurotransmission resulting in the suppression of the neuron maturation process and switching the GABAergic responses from excitatory to inhibitory, while the Satb2 deletion has a similar effect only in the Satb1-null mice. We show that the Satb1 and Satb2 transcription factors are involved in the regulation of the transmission of excitatory signals and inhibition of the neuronal network in the cortical cell culture.

Highlights

Neuronal transcription factors regulate the expression of many receptors and intracellular signaling molecules involved in excitatory neurotransmission [1,2]
Sci. 2021, 22, 5968 we found that the expression of Satb1 and Satb2 is necessary for the development of excitatory and inhibitory neurotransmission, and conditional knockout of these transcription factors induces alterations in the expression of glutamate receptors responsible for the excitation of neural cells and the inhibitory GABA(A) receptor
Satb2 is expressed in 42.3 ± 19% of neurons (Supplementary, Figure S3C), and its expression was not detected in GABA+ -neurons (Supplementary, Figure S3D)

Summary

Introduction

Neuronal transcription factors regulate the expression of many receptors and intracellular signaling molecules involved in excitatory neurotransmission [1,2]. The special AT-rich sequence-binding proteins 1 and 2 (Satb1/2) are nuclear matrix-associated proteins that exert multiple functions by influencing the structural organization of chromatin and interacting with several coactivators and co-repressors of transcription. Satb was first cloned from a cDNA library of the human cell line and found in thymocytes [3]. This factor was discovered in other tissues and cells. Satb functions as a highly pleiotropic regulator of gene expression which dynamically alters the organization and epigenetic status of the chromatin [4]. Changes in Satb expression are associated with human tumors, including rectal cancer, cutaneous malignant melanoma, breast and prostate epithelia [5,6,7]

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Results

Conclusion