Molecular and Behavior Relationship in Gene-Manipulated Model Organisms

A topical collection in Cells (ISSN 2073-4409). This collection belongs to the section "Cells of the Nervous System".

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Editor


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Collection Editor
Department of Molecular & Cellular Physiology, Shinshu University School of Medicine, Matsumoto 390-8621, Japan
Interests: neurodevelopmental disorders; CRISPR/Cas9; synaptic transmission; neuron

Topical Collection Information

Dear Colleagues,

Neuropsychiatric disorders, such as autism, epilepsy, schizophrenia, and Alzheimer’s disease, are primarily associated with a genetic predisposition. Over the past two decades, human genetic studies have identified candidate genes for the pathogenesis of these disorders. Behavioral studies using genetically modified animal models are widely used to verify the causal relationship between human mutations and disorders. Mice have been predominantly used as genetically modified disease models due to the ability of gene targeting in ES cells. In recent years, advances in genome editing technology have allowed recapitulating human mutations in various species, including worms, flies, fishes, rodents, and monkeys, and this enables us to study the large-scale collective behavior or higher cognitive functions. Viral-mediated region-specific gene manipulation also broadens the application of behavioral studies in various model organisms. In parallel, a wide variety of methods for behavioral studies combined with modern computer programming, such as machine learning, have also been established.

In this research topic, we invite original research articles or reviews related to behavioral studies using gene-manipulated model organisms. Research that is not directly related to diseases is also welcomed. We aim to share current advances and innovations in the research field.

Prof. Dr. Katsuhiko Tabuchi
Collection Editor

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Keywords

  • model organism
  • behavior
  • genome editing
  • neuropsychiatric disorders
  • CRISPR/Cas9

Published Papers (5 papers)

2023

Jump to: 2022, 2021

23 pages, 3659 KiB  
Article
Structural Analysis Implicates CASK-Liprin-α2 Interaction in Cerebellar Granular Cell Death in MICPCH Syndrome
by Qi Guo, Emi Kouyama-Suzuki, Yoshinori Shirai, Xueshan Cao, Toru Yanagawa, Takuma Mori and Katsuhiko Tabuchi
Cells 2023, 12(8), 1177; https://doi.org/10.3390/cells12081177 - 18 Apr 2023
Cited by 2 | Viewed by 2402
Abstract
Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However, the molecular mechanisms by which CASK deficiency causes cerebellar hypoplasia in this syndrome remain elusive. In this study, we used CASK [...] Read more.
Microcephaly with pontine and cerebellar hypoplasia (MICPCH) syndrome is a neurodevelopmental disorder caused by the deficiency of the X-chromosomal gene CASK. However, the molecular mechanisms by which CASK deficiency causes cerebellar hypoplasia in this syndrome remain elusive. In this study, we used CASK knockout (KO) mice as models for MICPCH syndrome and investigated the effect of CASK mutants. Female CASK heterozygote KO mice replicate the progressive cerebellar hypoplasia observed in MICPCH syndrome. CASK KO cultured cerebellar granule (CG) cells show progressive cell death that can be rescued by co-infection with lentivirus expressing wild-type CASK. Rescue experiments with CASK deletion mutants identify that the CaMK, PDZ, and SH3, but not L27 and guanylate kinase domains of CASK are required for the survival of CG cells. We identify missense mutations in the CaMK domain of CASK derived from human patients that fail to rescue the cell death of cultured CASK KO CG cells. Machine learning-based structural analysis using AlphaFold 2.2 predicts that these mutations disrupt the structure of the binding interface with Liprin-α2. These results suggest that the interaction with Liprin-α2 via the CaMK domain of CASK may be involved in the pathophysiology of cerebellar hypoplasia in MICPCH syndrome. Full article
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2022

Jump to: 2023, 2021

19 pages, 2796 KiB  
Article
Alterations of Serum Magnesium Concentration in Animal Models of Seizures and Epilepsy—The Effects of Treatment with a GPR39 Agonist and Knockout of the Gpr39 Gene
by Urszula Doboszewska, Jan Sawicki, Adam Sajnóg, Aleksandra Szopa, Anna Serefko, Katarzyna Socała, Mateusz Pieróg, Dorota Nieoczym, Katarzyna Mlyniec, Gabriel Nowak, Danuta Barałkiewicz, Ireneusz Sowa and Piotr Wlaź
Cells 2022, 11(13), 1987; https://doi.org/10.3390/cells11131987 - 21 Jun 2022
Cited by 6 | Viewed by 2475
Abstract
Several ligands have been proposed for the GPR39 receptor, including the element zinc. The relationship between GPR39 and magnesium homeostasis has not yet been examined, nor has such a relationship in the context of seizures/epilepsy. We used samples from mice that were treated [...] Read more.
Several ligands have been proposed for the GPR39 receptor, including the element zinc. The relationship between GPR39 and magnesium homeostasis has not yet been examined, nor has such a relationship in the context of seizures/epilepsy. We used samples from mice that were treated with an agonist of the GPR39 receptor (TC-G 1008) and underwent acute seizures (maximal electroshock (MES)- or 6-hertz-induced seizures) or a chronic, pentylenetetrazole (PTZ)-induced kindling model of epilepsy. MES seizures and PTZ kindling, unlike 6 Hz seizures, increased serum magnesium concentration. In turn, Gpr39-KO mice that underwent PTZ kindling displayed decreased concentrations of this element in serum, compared to WT mice subjected to this procedure. However, the levels of expression of TRPM7 and SlC41A1 proteins—which are responsible for magnesium transport into and out of cells, respectively—did not differ in the hippocampus between Gpr39-KO and WT mice. Furthermore, laser ablation inductively coupled plasma mass spectrometry applied to hippocampal slices did not reveal differences in magnesium levels between the groups. These data show the relationship between magnesium homeostasis and certain types of acute or chronic seizures (MES seizures or PTZ kindling, respectively), but do not explicitly support the role of GPR39 in mediating magnesium balance in the hippocampus in the latter model. However, decreased expression of TRPM7 and increased expression of SLC41A1—which were observed in the hippocampi of Gpr39-KO mice treated with TC-G 1008, in comparison to WT mice that received the same treatment—implicitly support the link between GPR39 and hippocampal magnesium homeostasis. Full article
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18 pages, 4799 KiB  
Review
The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model
by Konark Mukherjee, Leslie E. W. LaConte and Sarika Srivastava
Cells 2022, 11(7), 1131; https://doi.org/10.3390/cells11071131 - 28 Mar 2022
Cited by 5 | Viewed by 2999
Abstract
Most human disease manifests as a result of tissue pathology, due to an underlying disease process (pathogenesis), rather than the acute loss of specific molecular function(s). Successful therapeutic strategies thus may either target the correction of a specific molecular function or halt the [...] Read more.
Most human disease manifests as a result of tissue pathology, due to an underlying disease process (pathogenesis), rather than the acute loss of specific molecular function(s). Successful therapeutic strategies thus may either target the correction of a specific molecular function or halt the disease process. For the vast majority of brain diseases, clear etiologic and pathogenic mechanisms are still elusive, impeding the discovery or design of effective disease-modifying drugs. The development of valid animal models and their proper characterization is thus critical for uncovering the molecular basis of the underlying pathobiological processes of brain disorders. MICPCH (microcephaly and pontocerebellar hypoplasia) is a monogenic condition that results from variants of an X-linked gene, CASK (calcium/calmodulin-dependent serine protein kinase). CASK variants are associated with a wide range of clinical presentations, from lethality and epileptic encephalopathies to intellectual disabilities, microcephaly, and autistic traits. We have examined CASK loss-of-function mutations in model organisms to simultaneously understand the pathogenesis of MICPCH and the molecular function/s of CASK. Our studies point to a highly complex relationship between the potential molecular function/s of CASK and the phenotypes observed in model organisms and humans. Here we discuss the implications of our observations from the pathogenesis of MICPCH as a cautionary narrative against oversimplifying molecular interpretations of data obtained from genetically modified animal models of human diseases. Full article
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8 pages, 3155 KiB  
Communication
Genetic and Functional Differences between Duplicated Zebrafish Genes for Human SCN1A
by Wout J. Weuring, Jos W. Hoekman, Kees P. J. Braun and Bobby P. C. Koeleman
Cells 2022, 11(3), 454; https://doi.org/10.3390/cells11030454 - 28 Jan 2022
Cited by 2 | Viewed by 3157
Abstract
There are currently seven different zebrafish strains that model Dravet Syndrome, a severe childhood form of epilepsy. These models are based on a set of duplicated genes, scn1laa and scn1lab, which are the homologs for human SCN1A. Disrupting one of the [...] Read more.
There are currently seven different zebrafish strains that model Dravet Syndrome, a severe childhood form of epilepsy. These models are based on a set of duplicated genes, scn1laa and scn1lab, which are the homologs for human SCN1A. Disrupting one of the genes would mimic a heterozygous disease state in humans, as the paralog gene is still present. While this ‘disease-state model’ is widely accepted, there is also evidence that the function of these genes might not be completely the same. By analyzing the functional domains, we discovered several hotspots in the protein that are not conserved, indicating a functional difference. Based on this, we generated scn1Laa knockout zebrafish and compared their phenotype to scn1lab knockouts. The genetic and functional differences we discovered can have implications for the use of zebrafish as a model for Dravet Syndrome. Full article
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2021

Jump to: 2023, 2022

22 pages, 5698 KiB  
Article
IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex
by Anuradha Mehta, Yoshinori Shirai, Emi Kouyama-Suzuki, Mengyun Zhou, Takahiro Yoshizawa, Toru Yanagawa, Takuma Mori and Katsuhiko Tabuchi
Cells 2021, 10(10), 2724; https://doi.org/10.3390/cells10102724 - 12 Oct 2021
Cited by 15 | Viewed by 3558
Abstract
IQSEC2 is a guanine nucleotide exchange factor (GEF) for ADP-ribosylation factor 6 (Arf6), of which protein is exclusively localized to the postsynaptic density of the excitatory synapse. Human genome studies have revealed that the IQSEC2 gene is associated with X-linked neurodevelopmental disorders, such [...] Read more.
IQSEC2 is a guanine nucleotide exchange factor (GEF) for ADP-ribosylation factor 6 (Arf6), of which protein is exclusively localized to the postsynaptic density of the excitatory synapse. Human genome studies have revealed that the IQSEC2 gene is associated with X-linked neurodevelopmental disorders, such as intellectual disability (ID), epilepsy, and autism. In this study, we examined the behavior and synapse function in IQSEC2 knockout (KO) mice that we generated using CRIPSR/Cas9-mediated genome editing to solve the relevance between IQSEC2 deficiency and the pathophysiology of neurodevelopmental disorders. IQSEC2 KO mice exhibited autistic behaviors, such as overgrooming and social deficits. We identified that up-regulation of c-Fos expression in the medial prefrontal cortex (mPFC) induced by social stimulation was significantly attenuated in IQSEC2 KO mice. Whole cell electrophysiological recording identified that synaptic transmissions mediated by α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR), N-methyl-D-aspartate receptor (NMDAR), and γ-aminobutyric acid receptor (GABAR) were significantly decreased in pyramidal neurons in layer 5 of the mPFC in IQSEC2 KO mice. Reexpression of IQSEC2 isoform 1 in the mPFC of IQSEC2 KO mice using adeno-associated virus (AAV) rescued both synaptic and social deficits, suggesting that impaired synaptic function in the mPFC is responsible for social deficits in IQSEC2 KO mice. Full article
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