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Disorders in Brain Development and Nervous System: Key Molecules and Pathology

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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: 20 May 2024 | Viewed by 7326

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Prof. Dr. Kazuhiko Nakadate

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Department of Basic Science, Educational and Research Center for Pharmacy, Meiji Pharmaceutical University, Tokyo 204-8588, Japan
Interests: neuronal development; neuron-glia interaction; aminergic cells; synaptic plasticity; micronutrient
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Special Issue Information

Dear Colleagues,

Brain development is the biological process by which neurons are generated. And this process of neuronal development includes proliferation, differentiation, migration, axonal guidance, synaptogenesis, and neural network formation. Prenatal and postnatal brain development are very important for our later social life. During the prenatal and early postnatal period, brain growth is extremely rapid, and in humans, in just his first eight years after birth, the foundation for future learning and health can be laid. However, it is well known that neurons during this developmental stage respond to a myriad of chemical factors, nutritional status, toxins, infections, and many other factors. In the central nervous system, a myriad of chemical factors have been shown to impair not only neuronal differentiation and development, but also neural circuit formation, normal function and morphogenesis, and the association of neurons and glial cells. On the other hand, our brain continues to develop slowly and reach maturity, after which its function gradually weakens. During these times and throughout our lives, various factors affect the neurons in our brains. In recent years, it has become increasingly clear that changes in lifestyle habits and various environmental changes affect the neurons themselves or neural circuits in the brain.

It is necessary to investigate and elucidate the factors that affect the brain, and to analyze in detail how these factors affect the brain. This special issue of the journal calls for discussion of factors that influence prenatal, postnatal, and mature brain structure and function by many molecular factors, and the pathology of the affected brain.

Prof. Dr. Kazuhiko Nakadate
Guest Editor

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Keywords

neurogenesis
neurotrophic factors
synapse formation
neuronal circuit formation
nutrition
specific genes for brain development
pathology of the affected brain

Published Papers (5 papers)

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Research

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14 pages, 14972 KiB

Open AccessArticle

Brain-Specific Angiogenesis Inhibitor 3 Is Expressed in the Cochlea and Is Necessary for Hearing Function in Mice

by Chika Saegusa, Wataru Kakegawa, Eriko Miura, Takahiro Aimi, Sachiyo Mogi, Tatsuhiko Harada, Taku Yamashita, Michisuke Yuzaki and Masato Fujioka

Int. J. Mol. Sci. 2023, 24(23), 17092; https://doi.org/10.3390/ijms242317092 - 04 Dec 2023

Viewed by 1003

Abstract

Mammalian auditory hair cells transduce sound-evoked traveling waves in the cochlea into nerve stimuli, which are essential for hearing function. Pillar cells located between the inner and outer hair cells are involved in the formation of the tunnel of Corti, which incorporates outer-hair-cell-driven fluid oscillation and basilar membrane movement, leading to the fine-tuned frequency-specific perception of sounds by the inner hair cells. However, the detailed molecular mechanism underlying the development and maintenance of pillar cells remains to be elucidated. In this study, we examined the expression and function of brain-specific angiogenesis inhibitor 3 (Bai3), an adhesion G-protein-coupled receptor, in the cochlea. We found that Bai3 was expressed in hair cells in neonatal mice and pillar cells in adult mice, and, interestingly, Bai3 knockout mice revealed the abnormal formation of pillar cells, with the elevation of the hearing threshold in a frequency-dependent manner. Furthermore, old Bai3 knockout mice showed the degeneration of hair cells and spiral ganglion neurons in the basal turn. The results suggest that Bai3 plays a crucial role in the development and/or maintenance of pillar cells, which, in turn, are necessary for normal hearing function. Our results may contribute to understanding the mechanisms of hearing loss in human patients. Full article

(This article belongs to the Special Issue Disorders in Brain Development and Nervous System: Key Molecules and Pathology)

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17 pages, 3192 KiB

Open AccessArticle

Neonatal Exposure to Lipopolysaccharide Promotes Neurogenesis of Subventricular Zone Progenitors in the Developing Neocortex of Ferrets

by Kazuhiko Sawada, Shiori Kamiya and Tetsuya Kobayashi

Int. J. Mol. Sci. 2023, 24(19), 14962; https://doi.org/10.3390/ijms241914962 - 06 Oct 2023

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Abstract

Lipopolysaccharide (LPS) is a natural agonist of toll-like receptor 4 that serves a role in innate immunity. The current study evaluated the LPS-mediated regulation of neurogenesis in the subventricular zone (SVZ) progenitors, that is, the basal radial glia and intermediate progenitors (IPs), in ferrets. Ferret pups were subcutaneously injected with LPS (500 μg/g of body weight) on postnatal days (PDs) 6 and 7. Furthermore, 5-ethynyl-2′-deoxyuridine (EdU) and 5-bromo-2′-deoxyuridine (BrdU) were administered on PDs 5 and 7, respectively, to label the post-proliferative and proliferating cells in the inner SVZ (iSVZ) and outer SVZ (oSVZ). A significantly higher density of BrdU single-labeled proliferating cells was observed in the iSVZ of LPS-exposed ferrets than in controls but not in post-proliferative EdU single-labeled and EdU/BrdU double-labeled self-renewing cells. BrdU single-labeled cells exhibited a lower proportion of Tbr2 immunostaining in LPS-exposed ferrets (22.2%) than in controls (42.6%) and a higher proportion of Ctip2 immunostaining in LPS-exposed ferrets (22.2%) than in controls (8.6%). The present findings revealed that LPS modified the neurogenesis of SVZ progenitors. Neonatal LPS exposure facilitates the proliferation of SVZ progenitors, followed by the differentiation of Tbr2-expressing IPs into Ctip2-expressing immature neurons. Full article

(This article belongs to the Special Issue Disorders in Brain Development and Nervous System: Key Molecules and Pathology)

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14 pages, 1867 KiB

Open AccessArticle

Effectiveness of Albumin-Fused Thioredoxin against 6-Hydroxydopamine-Induced Neurotoxicity In Vitro

by Okina Sakakibara, Mikako Shimoda, Gaku Yamamoto, Youichirou Higashi, Mayumi Ikeda-Imafuku, Yu Ishima, Masahiro Kawahara and Ken-ichiro Tanaka

Int. J. Mol. Sci. 2023, 24(11), 9758; https://doi.org/10.3390/ijms24119758 - 05 Jun 2023

Cited by 2 | Viewed by 1357

Abstract

Parkinson’s disease (PD) is a neurodegenerative disorder caused by oxidative stress-dependent loss of dopaminergic neurons in the substantia nigra and elevated microglial inflammatory responses. Recent studies show that cell loss also occurs in the hypothalamus in PD. However, effective treatments for the disorder are lacking. Thioredoxin is the major protein disulfide reductase in vivo. We previously synthesized an albumin–thioredoxin fusion protein (Alb–Trx), which has a longer plasma half-life than thioredoxin, and reported its effectiveness in the treatment of respiratory and renal diseases. Moreover, we reported that the fusion protein inhibits trace metal-dependent cell death in cerebrovascular dementia. Here, we investigated the effectiveness of Alb–Trx against 6-hydroxydopamine (6-OHDA)-induced neurotoxicity in vitro. Alb–Trx significantly inhibited 6-OHDA-induced neuronal cell death and the integrated stress response. Alb–Trx also markedly inhibited 6-OHDA-induced reactive oxygen species (ROS) production, at a concentration similar to that inhibiting cell death. Exposure to 6-OHDA perturbed the mitogen-activated protein kinase pathway, with increased phosphorylated Jun N-terminal kinase and decreased phosphorylated extracellular signal-regulated kinase levels. Alb–Trx pretreatment ameliorated these changes. Furthermore, Alb–Trx suppressed 6-OHDA-induced neuroinflammatory responses by inhibiting NF-κB activation. These findings suggest that Alb–Trx reduces neuronal cell death and neuroinflammatory responses by ameliorating ROS-mediated disruptions in intracellular signaling pathways. Thus, Alb–Trx may have potential as a novel therapeutic agent for PD. Full article

(This article belongs to the Special Issue Disorders in Brain Development and Nervous System: Key Molecules and Pathology)

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30 pages, 4224 KiB

Open AccessArticle

Differential Early Mechanistic Frontal Lobe Responses to Choline Chloride and Soy Isoflavones in an Experimental Model of Fetal Alcohol Spectrum Disorder

by Suzanne M. de la Monte, Ming Tong and Busra Delikkaya

Int. J. Mol. Sci. 2023, 24(8), 7595; https://doi.org/10.3390/ijms24087595 - 20 Apr 2023

Viewed by 2035

Abstract

Fetal alcohol spectrum disorder (FASD) is the most common preventable cause of neurodevelopmental defects, and white matter is a major target of ethanol neurotoxicity. Therapeutic interventions with choline or dietary soy could potentially supplement public health preventive measures. However, since soy contains abundant choline, it would be important to know if its benefits are mediated by choline or isoflavones. We compared early mechanistic responses to choline and the Daidzein+Genistein (D+G) soy isoflavones in an FASD model using frontal lobe tissue to assess oligodendrocyte function and Akt-mTOR signaling. Long Evans rat pups were binge administered 2 g/Kg of ethanol or saline (control) on postnatal days P3 and P5. P7 frontal lobe slice cultures were treated with vehicle (Veh), Choline chloride (Chol; 75 µM), or D+G (1 µM each) for 72 h without further ethanol exposures. The expression levels of myelin oligodendrocyte proteins and stress-related molecules were measured by duplex enzyme-linked immunosorbent assays (ELISAs), and mTOR signaling proteins and phosphoproteins were assessed using 11-plex magnetic bead-based ELISAs. Ethanol’s main short-term effects in Veh-treated cultures were to increase GFAP and relative PTEN phosphorylation and reduce Akt phosphorylation. Chol and D+G significantly modulated the expression of oligodendrocyte myelin proteins and mediators of insulin/IGF-1-Akt-mTOR signaling in both control and ethanol-exposed cultures. In general, the responses were more robust with D+G; the main exception was that RPS6 phosphorylation was significantly increased by Chol and not D+G. The findings suggest that dietary soy, with the benefits of providing complete nutrition together with Choline, could be used to help optimize neurodevelopment in humans at risk for FASD. Full article

(This article belongs to the Special Issue Disorders in Brain Development and Nervous System: Key Molecules and Pathology)

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Review

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17 pages, 4733 KiB

Open AccessReview

Advanced Techniques Using In Vivo Electroporation to Study the Molecular Mechanisms of Cerebral Development Disorders

by Chen Yang, Atsunori Shitamukai, Shucai Yang and Ayano Kawaguchi

Int. J. Mol. Sci. 2023, 24(18), 14128; https://doi.org/10.3390/ijms241814128 - 15 Sep 2023

Viewed by 1148

Abstract

The mammalian cerebral cortex undergoes a strictly regulated developmental process. Detailed in situ visualizations, imaging of these dynamic processes, and in vivo functional gene studies significantly enhance our understanding of brain development and related disorders. This review introduces basic techniques and recent advancements in in vivo electroporation for investigating the molecular mechanisms underlying cerebral diseases. In utero electroporation (IUE) is extensively used to visualize and modify these processes, including the forced expression of pathological mutants in human diseases; thus, this method can be used to establish animal disease models. The advent of advanced techniques, such as genome editing, including de novo knockout, knock-in, epigenetic editing, and spatiotemporal gene regulation, has further expanded our list of investigative tools. These tools include the iON expression switch for the precise control of timing and copy numbers of exogenous genes and TEMPO for investigating the temporal effects of genes. We also introduce the iGONAD method, an improved genome editing via oviductal nucleic acid delivery approach, as a novel genome-editing technique that has accelerated brain development exploration. These advanced in vivo electroporation methods are expected to provide valuable insights into pathological conditions associated with human brain disorders. Full article

(This article belongs to the Special Issue Disorders in Brain Development and Nervous System: Key Molecules and Pathology)

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