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Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors
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Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors

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 January 2023) | Viewed by 26408

Special Issue Editors

Dr. Mario Costa

E-Mail Website
Guest Editor
Institute of Neuroscience, Italian National Research Council (IN-CNR), 56124 Pisa, Italy
Interests: FOXG1-related disorders; Rett syndrome; neurodevelopmental disorders; brain cancer; glioblastoma; cell signaling
Dr. Eleonora Vannini

E-Mail Website
Co-Guest Editor
1. Neuroscience Institute, National Research Council (CNR), 56124 Pisa, Italy
2. Centro Pisano Ricerca e Implementazione Clinica Flash Radiotherapy “CPFR@CISUP”, “S. Chiara” Hospital, 56126 Pisa, Italy
Interests: neuroncology; epilepsy; cortical plasticity; visual system; bacterial toxins
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleague,

The correct morphofunctional shaping and function of the central nervous system (CNS) requires a continuous interaction between intrinsic (genes/molecules expressed within the tissue) and extrinsic (e.g., neural activity) factors at all developmental stages including the adulthoods. Any significant deviation from the normal CNS functions due to social deprivation, environmental factors, genetic and metabolic diseases, immune disorders, infectious diseases or nutritional factors results in abnormal neuronal architecture or connectivity. In this scenario, stem cell self-renewal and differentiation play an important role not only in normal neurodevelopment, but also in brain tumours’ establishment. An example are the stem cells, considered responsible of sustaining tumour growth. These cells emphasized the importance of understanding the cellular dynamics and the molecular pathways regulating neural cell fate. In this Research Topic, we aim at providing a collection of high-impact papers dissecting which cellular and molecular mechanisms are involved into the onset of brain tumour and neurodevelopmental disorders. Accordingly, Original Research or Review articles describing which signalling or specific treatment influence physiologic functions such as neuronal development and CNS tumours will be considered.

Prof. Dr. Mario Costa
Guest Editors
Dr. Eleonora Vannini
Co-Guest Editors

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Keywords

  • Neurodevelopmental disorders
  • Brain tumours
  • Antitumor drugs
  • Tumoral stem cells
  • FOXG1 related disorders

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Published Papers (7 papers)

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Editorial

Jump to: Research, Review

3 pages, 175 KiB  
Editorial
Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors
by Mario Costa and Eleonora Vannini
Int. J. Mol. Sci. 2023, 24(11), 9469; https://doi.org/10.3390/ijms24119469 - 30 May 2023
Viewed by 1249
Abstract
The normal growth and operation of the central nervous system (CNS) at all stages of development, including adulthood, depend on the interaction between intrinsic and extrinsic factors [...] Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors)

Research

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22 pages, 1077 KiB  
Article
RNAseq Analysis of FABP4 Knockout Mouse Hippocampal Transcriptome Suggests a Role for WNT/β-Catenin in Preventing Obesity-Induced Cognitive Impairment
by Simon W. So, Joshua P. Nixon, David A. Bernlohr and Tammy A. Butterick
Int. J. Mol. Sci. 2023, 24(4), 3381; https://doi.org/10.3390/ijms24043381 - 8 Feb 2023
Cited by 5 | Viewed by 3404
Abstract
Microglial fatty-acid binding protein 4 (FABP4) is a regulator of neuroinflammation. We hypothesized that the link between lipid metabolism and inflammation indicates a role for FABP4 in regulating high fat diet (HFD)-induced cognitive decline. We have previously shown that obese FABP4 knockout mice [...] Read more.
Microglial fatty-acid binding protein 4 (FABP4) is a regulator of neuroinflammation. We hypothesized that the link between lipid metabolism and inflammation indicates a role for FABP4 in regulating high fat diet (HFD)-induced cognitive decline. We have previously shown that obese FABP4 knockout mice exhibit decreased neuroinflammation and cognitive decline. FABP4 knockout and wild type mice were fed 60% HFD for 12 weeks starting at 15 weeks old. Hippocampal tissue was dissected and RNA-seq was performed to measure differentially expressed transcripts. Reactome molecular pathway analysis was utilized to examine differentially expressed pathways. Results showed that HFD-fed FABP4 knockout mice have a hippocampal transcriptome consistent with neuroprotection, including associations with decreased proinflammatory signaling, ER stress, apoptosis, and cognitive decline. This is accompanied by an increase in transcripts upregulating neurogenesis, synaptic plasticity, long-term potentiation, and spatial working memory. Pathway analysis revealed that mice lacking FABP4 had changes in metabolic function that support reduction in oxidative stress and inflammation, and improved energy homeostasis and cognitive function. Analysis suggested a role for WNT/β-Catenin signaling in the protection against insulin resistance, alleviating neuroinflammation and cognitive decline. Collectively, our work shows that FABP4 represents a potential target in alleviating HFD-induced neuroinflammation and cognitive decline and suggests a role for WNT/β-Catenin in this protection. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors)
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14 pages, 5559 KiB  
Article
LIF–IGF Axis Contributes to the Proliferation of Neural Progenitor Cells in Developing Rat Cerebrum
by Sho Takata, Hiromi Sakata-Haga, Hiroki Shimada, Tsuyoshi Tsukada, Daisuke Sakai, Hiroki Shoji, Mitsuhiro Tomosugi, Yuka Nakamura, Yasuhito Ishigaki, Hideaki Iizuka, Yasuhiko Hayashi and Toshihisa Hatta
Int. J. Mol. Sci. 2022, 23(21), 13199; https://doi.org/10.3390/ijms232113199 - 30 Oct 2022
Cited by 5 | Viewed by 2087
Abstract
In rodent models, leukemia inhibitory factor (LIF) is involved in cerebral development via the placenta, and maternal immune activation is linked to psychiatric disorders in the child. However, whether LIF acts directly on neural progenitor cells (NPCs) remains unclear. This study performed DNA [...] Read more.
In rodent models, leukemia inhibitory factor (LIF) is involved in cerebral development via the placenta, and maternal immune activation is linked to psychiatric disorders in the child. However, whether LIF acts directly on neural progenitor cells (NPCs) remains unclear. This study performed DNA microarray analysis and quantitative RT-PCR on the fetal cerebrum after maternal intraperitoneal or fetal intracerebral ventricular injection of LIF at day 14.5 (E14.5) and determined that the expression of insulin-like growth factors (IGF)-1 and -2 was induced by LIF. Physiological IGF-1 and IGF-2 levels in fetal cerebrospinal fluid (CSF) increased from E15.5 to E17.5, following the physiological surge of LIF levels in CSF at E15.5. Immunostaining showed that IGF-1 was expressed in the cerebrum at E15.5 to E19.5 and IGF-2 at E15.5 to E17.5 and that IGF-1 receptor and insulin receptor were co-expressed in NPCs. Further, LIF treatment enhanced cultured NPC proliferation, which was reduced by picropodophyllin, an IGF-1 receptor inhibitor, even under LIF supplementation. Our findings suggest that IGF expression and release from the NPCs of the fetal cerebrum in fetal CSF is induced by LIF, thus supporting the involvement of the LIF–IGF axis in cerebral cortical development in an autocrine/paracrine manner. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors)
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17 pages, 2524 KiB  
Article
The Autism Spectrum Disorder-Associated Bacterial Metabolite p-Cresol Derails the Neuroimmune Response of Microglial Cells Partially via Reduction of ADAM17 and ADAM10
by Yuanpeng Zheng, Naika Z. Prince, Lucia N. Peralta Marzal, Sabbir Ahmed, Johan Garssen, Paula Perez Pardo and Aletta D. Kraneveld
Int. J. Mol. Sci. 2022, 23(19), 11013; https://doi.org/10.3390/ijms231911013 - 20 Sep 2022
Cited by 9 | Viewed by 3921
Abstract
The bacterial metabolite 4-methylphenol (para-cresol or p-cresol) and its derivative p-cresyl sulfate (pCS) are elevated in the urine and feces of children with autism spectrum disorder (ASD). It has been shown that p-cresol administration induces social [...] Read more.
The bacterial metabolite 4-methylphenol (para-cresol or p-cresol) and its derivative p-cresyl sulfate (pCS) are elevated in the urine and feces of children with autism spectrum disorder (ASD). It has been shown that p-cresol administration induces social behavior deficits and repetitive behavior in mice. However, the mechanisms of p-cresol, specifically its metabolite pCS that can reach the brain, in ASD remain to be investigated. The pCS has been shown to inhibit LPS-stimulated inflammatory response. A Disintegrin And Metalloprotease 10 (ADAM10) and A Disintegrin And Metalloprotease 17 (ADAM17) are thought to regulate microglial immune response by cleaving membrane-bound proteins. In the present study, a neuroinflammation model of LPS-activated BV2 microglia has been used to unveil the potential molecular mechanism of pCS in ASD pathogenesis. In microglial cells pCS treatment decreases the expression or maturation of ADAM10 and ADAM17. In addition, pCS treatment attenuates TNF-α and IL-6 releases as well as phagocytosis activity of microglia. In in vitro ADAM10/17 inhibition experiments, either ADAM10 or ADAM17 inhibition reduces constitutive and LPS-activated release of TNF-α, TNFR-1 and IL-6R by microglial cells, while it increases constitutive and LPS-activated microglial phagocytotic activity. The in vivo results further confirm the involvement of ADAM10 and ADAM17 in ASD pathogenesis. In in utero VPA-exposed male mice, elevated concentration in serum of p-cresol-associated metabolites pCS and p-cresyl glucuronide (pCG) is associated with a VPA-induced increased ADAM10 maturation, and a decreased ADAM17 maturation that is related with attenuated levels of soluble TNF-α and TGF-β1 in the mice brain. Overall, the present study demonstrates a partial role of ADAM10 and ADAM17 in the derailed innate immune response of microglial cells associated with pCS-induced ASD pathogenesis. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors)
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17 pages, 8132 KiB  
Article
Dual Profile of Environmental Enrichment and Autistic-Like Behaviors in the Maternal Separated Model in Rats
by Monireh Mansouri, Hamidreza Pouretemad, Gregers Wegener, Mehrdad Roghani, Masoud Afshari, Carina Mallard and Maryam Ardalan
Int. J. Mol. Sci. 2021, 22(3), 1173; https://doi.org/10.3390/ijms22031173 - 25 Jan 2021
Cited by 16 | Viewed by 4240
Abstract
Background: Environmental Enrichment (EE) has been suggested as a possible therapeutic intervention for neurodevelopmental disorders such as autism. Although the benefits of this therapeutic method have been reported in some animal models and human studies, the unknown pathophysiology of autism as well [...] Read more.
Background: Environmental Enrichment (EE) has been suggested as a possible therapeutic intervention for neurodevelopmental disorders such as autism. Although the benefits of this therapeutic method have been reported in some animal models and human studies, the unknown pathophysiology of autism as well as number of conflicting results, urge for further examination of the therapeutic potential of EE in autism. Therefore, the aim of this study was to examine the effects of environmental enrichment on autism-related behaviors which were induced in the maternal separation (MS) animal model. Material and Methods: Maternally separated (post-natal day (PND) 1–14, 3 h/day) and control male rats were at weaning (PND21) age equally divided into rats housed in enriched environment and normal environment. At adolescence (PND42–50), the four groups were behaviorally tested for direct social interaction, sociability, repetitive behaviors, anxiety behavior, and locomotion. Following completion of the behavioral tests, the blood and brain tissue samples were harvested in order to assess plasma level of brain derived neurotrophic factor (BDNF) and structural plasticity of brain using ELISA and stereological methods respectively. Results: We found that environmental enrichment reduced repetitive behaviors but failed to improve the impaired sociability and anxiety behaviors which were induced by maternal separation. Indeed, EE exacerbated anxiety and social behaviors deficits in association with increased plasma BDNF level, larger volume of the hippocampus and infra-limbic region and higher number of neurons in the infra-limbic area (p < 0.05). Conclusion: We conclude that environmental enrichment has a significant improvement effect on the repetitive behavior as one of the core autistic-like behaviors induced by maternal separation but has negative effect on the anxiety and social behaviors which might have been modulated by BDNF. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors)
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Review

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27 pages, 7025 KiB  
Review
Transcription Factors with Targeting Potential in Gliomas
by Angeliki-Ioanna Giannopoulou, Dimitrios S. Kanakoglou and Christina Piperi
Int. J. Mol. Sci. 2022, 23(7), 3720; https://doi.org/10.3390/ijms23073720 - 28 Mar 2022
Cited by 18 | Viewed by 4814
Abstract
Gliomas portray a large and heterogeneous group of CNS tumors, encompassing a wide range of low- to high-grade tumors, as defined by histological and molecular characteristics. The identification of signature mutations and other molecular abnormalities has largely impacted tumor classification, diagnosis, and therapy. [...] Read more.
Gliomas portray a large and heterogeneous group of CNS tumors, encompassing a wide range of low- to high-grade tumors, as defined by histological and molecular characteristics. The identification of signature mutations and other molecular abnormalities has largely impacted tumor classification, diagnosis, and therapy. Transcription factors (TFs) are master regulators of gene expression programs, which ultimately shape cell fate and homeostasis. A variety of TFs have been detected to be aberrantly expressed in brain tumors, being highly implicated in critical pathological aspects and progression of gliomas. Herein, we describe a selection of oncogenic (GLI-1/2/3, E2F1–8, STAT3, and HIF-1/2) and tumor suppressor (NFI-A/B, TBXT, MYT1, and MYT1L) TFs that are deregulated in gliomas and are subsequently associated with tumor development, progression, and migratory potential. We further discuss the current targeting options against these TFs, including chemical (Bortezomib) and natural (Plumbagin) compounds, small molecules, and inhibitors, and address their potential implications in glioma therapy. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors)
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18 pages, 2605 KiB  
Review
Contribution of “Omic” Studies to the Understanding of Cadasil. A Systematic Review
by Elena Muiño, Israel Fernández-Cadenas and Adrià Arboix
Int. J. Mol. Sci. 2021, 22(14), 7357; https://doi.org/10.3390/ijms22147357 - 8 Jul 2021
Cited by 18 | Viewed by 5525
Abstract
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main [...] Read more.
CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor β (TGFβ) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets. Full article
(This article belongs to the Special Issue Cellular and Molecular Mechanisms in Neurodevelopmental Disorders and Brain Tumors)
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