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Role of Gene Expression in the Physiology and Pathology of Neurons

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: closed (31 May 2020) | Viewed by 56108

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Prof. Dr. Jacopo Meldolesi

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1. San Raffaele Institute, Vita-Salute San Raffaele University, 20132 Milan, Italy
2. CNR Institute of Neuroscience, Milan-Bicocca University, 20132 Milan, Italy
Interests: neurons and their interactions with astrocytes; neurotrophin receptors; multiplicity and complexity of extracellular vesicles; non-secretory exocytosis; multiple roles of Ca²; control of gene expression; specificity of neural gene expression; neurodegenerative diseases and new therapies; synaptic pathology; astrocytes, microglia and their role in brain pathology
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Dear Colleagues,

Knowledge about the critical role of transcription factors in neural cells, especially those of the brain, is widely accepted. Relevance is not limited only to the specification and development. It includes many properties of neurons, from neurogenesis and differentiation with acquisition and maintenance of the identity, to various lesions, reprogramming, and regeneration. Also important is the role of genes in the development of diseases and the growing relevance of therapies, studied and developed in the course of recent, and also future, times. In order to provide a general view of the SI provided by the present imagination, I am adding a list of sections below already identified, destined to be expanded before the initiation of the enterprise:

Neuronal development;
Role of Myt1 and related transcription factors in neurogenesis;
Acquisition and maintenance of neuronal identity;
Regulation of dopaminergic neuron differentiation by transcription factors and miRNAs;
Mechanisms of Myt1 action in neuronal fate and glioblastoma proliferation;
Neuronal reprogramming, essential for tissue repair and regeneration;
Neuron, axon and synapse function and regeneration;
Diseases: Alzheimer’s and Parkinson’s diseases;
Conversion of neurons to and from other types of cells.

We now welcome additional articles concerning the topics outlined above and/or related to the key words listed below. Both original research and comprehensive review are welcomed.

Prof. Dr. Jacopo Meldolesi
Guest Editor

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Keywords

gene transcription
gene expression
neurogenesis
neuronal identification
neuronal development, differentiation and reprogramming
neuronal migration
axonal regeneration
synapses
astrocyte–neutron interactions
conversion of non-neural cells into neurons
neurodegenerative diseases
schizophrenia

Related Special Issue

Physiology and Pathology of Neurons 2.0 in International Journal of Molecular Sciences (3 articles)

Published Papers (10 papers)

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Editorial

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2 pages, 146 KiB

Open AccessEditorial

Gene Expression in the Physiology and Pathology of Neurons

by Jacopo Meldolesi

Int. J. Mol. Sci. 2020, 21(16), 5716; https://doi.org/10.3390/ijms21165716 - 10 Aug 2020

Viewed by 1969

Abstract

The expression of genes is the first process governing the molecular and structural specificity of the various types of cells, initiated by their transcription into the corresponding pre-mRNA [...] Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

Research

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12 pages, 2766 KiB

Open AccessArticle

WNT3A Promotes Neuronal Regeneration upon Traumatic Brain Injury

by Chu-Yuan Chang, Min-Zong Liang, Ching-Chih Wu, Pei-Yuan Huang, Hong-I Chen, Shaw-Fang Yet, Jin-Wu Tsai, Cheng-Fu Kao and Linyi Chen

Int. J. Mol. Sci. 2020, 21(4), 1463; https://doi.org/10.3390/ijms21041463 - 21 Feb 2020

Cited by 15 | Viewed by 4943

Abstract

The treatment of traumatic brain injury (TBI) remains a challenge due to limited knowledge about the mechanisms underlying neuronal regeneration. This current study compared the expression of WNT genes during regeneration of injured cortical neurons. Recombinant WNT3A showed positive effect in promoting neuronal regeneration via in vitro, ex vivo, and in vivo TBI models. Intranasal administration of WNT3A protein to TBI mice increased the number of NeuN⁺ neurons without affecting GFAP⁺ glial cells, compared to control mice, as well as retained motor function based on functional behavior analysis. Our findings demonstrated that WNT3A, 8A, 9B, and 10A promote regeneration of injured cortical neurons. Among these WNTs, WNT3A showed the most promising regenerative potential in vivo, ex vivo, and in vitro. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

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18 pages, 5367 KiB

Open AccessArticle

Synaptotagmin 1 Is Involved in Neuropathic Pain and Electroacupuncture-Mediated Analgesic Effect

by Juan Wan, Sha Nan, Jingjing Liu, Mingxing Ding, Hongmei Zhu, Chuanguang Suo, Zhuole Wang, Manli Hu, Dehai Wang and Yi Ding

Int. J. Mol. Sci. 2020, 21(3), 968; https://doi.org/10.3390/ijms21030968 - 31 Jan 2020

Cited by 16 | Viewed by 3318

Abstract

Numerous studies have verified that electroacupuncture (EA) can relieve neuropathic pain through a variety of mechanisms. Synaptotagmin 1 (Syt-1), a synaptic vesicle protein for regulating exocytosis of neurotransmitters, was found to be affected by EA stimulation. However, the roles of Syt-1 in neuropathic pain and EA-induced analgesic effect remain unclear. Here, the effect of Syt-1 on nociception was assessed through an antibody blockade, siRNA silencing, and lentivirus-mediated overexpression of spinal Syt-1 in rats with spared nerve injury (SNI). EA was used for stimulating bilateral “Sanjinjiao” and “Zusanli” acupoints of the SNI rats to evaluate its effect on nociceptive thresholds and spinal Syt-1 expression. The mechanically and thermally nociceptive behaviors were assessed with paw withdrawal threshold (PWT) and paw withdrawal latency (PWL) at different temperatures, respectively, at day 0, 7, 8, 14, and 20. Syt-1 mRNA and protein levels were determined with qRT-PCR and Western blot, respectively, and its distribution was observed with the immunohistochemistry method. The results demonstrated Syt-1 antibody blockade and siRNA silencing increased ipsilateral PWTs and PWLs of SNI rats, while Syt-1 overexpression decreased ipsilateral PWTs and PWLs of rats. EA significantly attenuated nociceptive behaviors and down-regulated spinal Syt-1 protein levels (especially in laminae I-II), which were reversed by Syt-1 overexpression. Our findings firstly indicate that Syt-1 is involved in the development of neuropathic pain and that EA attenuates neuropathic pain, probably through suppressing Syt-1 protein expression in the spinal cord. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

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Review

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21 pages, 2686 KiB

Open AccessReview

Regulation of Adult Neurogenesis in Mammalian Brain

by Maria Victoria Niklison-Chirou, Massimiliano Agostini, Ivano Amelio and Gerry Melino

Int. J. Mol. Sci. 2020, 21(14), 4869; https://doi.org/10.3390/ijms21144869 - 9 Jul 2020

Cited by 77 | Viewed by 16784

Abstract

Adult neurogenesis is a multistage process by which neurons are generated and integrated into existing neuronal circuits. In the adult brain, neurogenesis is mainly localized in two specialized niches, the subgranular zone (SGZ) of the dentate gyrus and the subventricular zone (SVZ) adjacent to the lateral ventricles. Neurogenesis plays a fundamental role in postnatal brain, where it is required for neuronal plasticity. Moreover, perturbation of adult neurogenesis contributes to several human diseases, including cognitive impairment and neurodegenerative diseases. The interplay between extrinsic and intrinsic factors is fundamental in regulating neurogenesis. Over the past decades, several studies on intrinsic pathways, including transcription factors, have highlighted their fundamental role in regulating every stage of neurogenesis. However, it is likely that transcriptional regulation is part of a more sophisticated regulatory network, which includes epigenetic modifications, non-coding RNAs and metabolic pathways. Here, we review recent findings that advance our knowledge in epigenetic, transcriptional and metabolic regulation of adult neurogenesis in the SGZ of the hippocampus, with a special attention to the p53-family of transcription factors. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

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20 pages, 1698 KiB

Open AccessReview

Acquisition of the Midbrain Dopaminergic Neuronal Identity

by Simone Mesman and Marten P. Smidt

Int. J. Mol. Sci. 2020, 21(13), 4638; https://doi.org/10.3390/ijms21134638 - 30 Jun 2020

Cited by 29 | Viewed by 4388

Abstract

The mesodiencephalic dopaminergic (mdDA) group of neurons comprises molecularly distinct subgroups, of which the substantia nigra (SN) and ventral tegmental area (VTA) are the best known, due to the selective degeneration of the SN during Parkinson’s disease. However, although significant research has been conducted on the molecular build-up of these subsets, much is still unknown about how these subsets develop and which factors are involved in this process. In this review, we aim to describe the life of an mdDA neuron, from specification in the floor plate to differentiation into the different subsets. All mdDA neurons are born in the mesodiencephalic floor plate under the influence of both SHH-signaling, important for floor plate patterning, and WNT-signaling, involved in establishing the progenitor pool and the start of the specification of mdDA neurons. Furthermore, transcription factors, like Ngn2, Ascl1, Lmx1a, and En1, and epigenetic factors, like Ezh2, are important in the correct specification of dopamine (DA) progenitors. Later during development, mdDA neurons are further subdivided into different molecular subsets by, amongst others, Otx2, involved in the specification of subsets in the VTA, and En1, Pitx3, Lmx1a, and WNT-signaling, involved in the specification of subsets in the SN. Interestingly, factors involved in early specification in the floor plate can serve a dual function and can also be involved in subset specification. Besides the mdDA group of neurons, other systems in the embryo contain different subsets, like the immune system. Interestingly, many factors involved in the development of mdDA neurons are similarly involved in immune system development and vice versa. This indicates that similar mechanisms are used in the development of these systems, and that knowledge about the development of the immune system may hold clues for the factors involved in the development of mdDA neurons, which may be used in culture protocols for cell replacement therapies. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

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19 pages, 1640 KiB

Open AccessReview

Transcriptional Regulators and Human-Specific/Primate-Specific Genes in Neocortical Neurogenesis

by Samir Vaid and Wieland B. Huttner

Int. J. Mol. Sci. 2020, 21(13), 4614; https://doi.org/10.3390/ijms21134614 - 29 Jun 2020

Cited by 19 | Viewed by 5409

Abstract

During development, starting from a pool of pluripotent stem cells, tissue-specific genetic programs help to shape and develop functional organs. To understand the development of an organ and its disorders, it is important to understand the spatio-temporal dynamics of the gene expression profiles that occur during its development. Modifications in existing genes, the de-novo appearance of new genes, or, occasionally, even the loss of genes, can greatly affect the gene expression profile of any given tissue and contribute to the evolution of organs or of parts of organs. The neocortex is evolutionarily the most recent part of the brain, it is unique to mammals, and is the seat of our higher cognitive abilities. Progenitors that give rise to this tissue undergo sequential waves of differentiation to produce the complete sets of neurons and glial cells that make up a functional neocortex. We will review herein our understanding of the transcriptional regulators that control the neural precursor cells (NPCs) during the generation of the most abundant class of neocortical neurons, the glutametergic neurons. In addition, we will discuss the roles of recently-identified human- and primate-specific genes in promoting neurogenesis, leading to neocortical expansion. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

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17 pages, 354 KiB

Open AccessReview

Neuronal Reprogramming for Tissue Repair and Neuroregeneration

by Roxanne Hsiang-Chi Liou, Thomas L. Edwards, Keith R. Martin and Raymond Ching-Bong Wong

Int. J. Mol. Sci. 2020, 21(12), 4273; https://doi.org/10.3390/ijms21124273 - 16 Jun 2020

Cited by 5 | Viewed by 3338

Abstract

Stem cell and cell reprogramming technology represent a rapidly growing field in regenerative medicine. A number of novel neural reprogramming methods have been established, using pluripotent stem cells (PSCs) or direct reprogramming, to efficiently derive specific neuronal cell types for therapeutic applications. Both in vitro and in vivo cellular reprogramming provide diverse therapeutic pathways for modeling neurological diseases and injury repair. In particular, the retina has emerged as a promising target for clinical application of regenerative medicine. Herein, we review the potential of neuronal reprogramming to develop regenerative strategy, with a particular focus on treating retinal degenerative diseases and discuss future directions and challenges in the field. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

19 pages, 1835 KiB

Open AccessReview

Molecular Regulation in Dopaminergic Neuron Development. Cues to Unveil Molecular Pathogenesis and Pharmacological Targets of Neurodegeneration

by Floriana Volpicelli, Carla Perrone-Capano, Gian Carlo Bellenchi, Luca Colucci-D’Amato and Umberto di Porzio

Int. J. Mol. Sci. 2020, 21(11), 3995; https://doi.org/10.3390/ijms21113995 - 3 Jun 2020

Cited by 17 | Viewed by 4596

Abstract

The relatively few dopaminergic neurons in the mammalian brain are mostly located in the midbrain and regulate many important neural functions, including motor integration, cognition, emotive behaviors and reward. Therefore, alteration of their function or degeneration leads to severe neurological and neuropsychiatric diseases. Unraveling the mechanisms of midbrain dopaminergic (mDA) phenotype induction and maturation and elucidating the role of the gene network involved in the development and maintenance of these neurons is of pivotal importance to rescue or substitute these cells in order to restore dopaminergic functions. Recently, in addition to morphogens and transcription factors, microRNAs have been identified as critical players to confer mDA identity. The elucidation of the gene network involved in mDA neuron development and function will be crucial to identify early changes of mDA neurons that occur in pre-symptomatic pathological conditions, such as Parkinson’s disease. In addition, it can help to identify targets for new therapies and for cell reprogramming into mDA neurons. In this essay, we review the cascade of transcriptional and posttranscriptional regulation that confers mDA identity and regulates their functions. Additionally, we highlight certain mechanisms that offer important clues to unveil molecular pathogenesis of mDA neuron dysfunction and potential pharmacological targets for the treatment of mDA neuron dysfunction. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

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13 pages, 909 KiB

Open AccessReview

Alternative Splicing by NOVA Factors: From Gene Expression to Cell Physiology and Pathology

by Jacopo Meldolesi

Int. J. Mol. Sci. 2020, 21(11), 3941; https://doi.org/10.3390/ijms21113941 - 30 May 2020

Cited by 23 | Viewed by 3658

Abstract

NOVA1 and NOVA2, the two members of the NOVA family of alternative splicing factors, bind YCAY clusters of pre-mRNAs and assemble spliceosomes to induce the maintenance/removal of introns and exons, thus governing the development of mRNAs. Members of other splicing families operate analogously. Activity of NOVAs accounts for up to 700 alternative splicing events per cell, taking place both in the nucleus (co-transcription of mRNAs) and in the cytoplasm. Brain neurons express high levels of NOVAs, with NOVA1 predominant in cerebellum and spinal cord, NOVA2 in the cortex. Among brain physiological processes NOVAs play critical roles in axon pathfinding and spreading, structure and function of synapses, as well as the regulation of surface receptors and voltage-gated channels. In pathology, NOVAs contribute to neurodegenerative diseases and epilepsy. In vessel endothelial cells, NOVA2 is essential for angiogenesis, while in adipocytes, NOVA1 contributes to regulation of thermogenesis and obesity. In many cancers NOVA1 and also NOVA2, by interacting with specific miRNAs and by additional mechanisms, activate oncogenic roles promoting cell proliferation, colony formation, migration, and invasion. In conclusion, NOVAs regulate cell functions of physiological and pathological nature. Single cell identification and distinction, and new therapies addressed to NOVA targets might be developed in the near future. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

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18 pages, 1225 KiB

Open AccessReview

Expression of Genes Involved in Axon Guidance: How Much Have We Learned?

by Sung Wook Kim and Kyong-Tai Kim

Int. J. Mol. Sci. 2020, 21(10), 3566; https://doi.org/10.3390/ijms21103566 - 18 May 2020

Cited by 13 | Viewed by 7106

Abstract

Neuronal axons are guided to their target during the development of the brain. Axon guidance allows the formation of intricate neural circuits that control the function of the brain, and thus the behavior. As the axons travel in the brain to find their target, they encounter various axon guidance cues, which interact with the receptors on the tip of the growth cone to permit growth along different signaling pathways. Although many scientists have performed numerous studies on axon guidance signaling pathways, we still have an incomplete understanding of the axon guidance system. Lately, studies on axon guidance have shifted from studying the signal transduction pathways to studying other molecular features of axon guidance, such as the gene expression. These new studies present evidence for different molecular features that broaden our understanding of axon guidance. Hence, in this review we will introduce recent studies that illustrate different molecular features of axon guidance. In particular, we will review literature that demonstrates how axon guidance cues and receptors regulate local translation of axonal genes and how the expression of guidance cues and receptors are regulated both transcriptionally and post-transcriptionally. Moreover, we will highlight the pathological relevance of axon guidance molecules to specific diseases. Full article

(This article belongs to the Special Issue Role of Gene Expression in the Physiology and Pathology of Neurons)

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