Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish
Abstract
:1. Introduction
1.1. Definition and Epidemiology of Autism Spectrum Disorders
1.2. Aetiology of Autism Spectrum Disorders
1.3. Diagnostic of Autism Spectrum Disorders
1.4. Treatment of Autism Spectrum Disorders
2. Genome Editing Systems, a Promising Tool for Modeling Human Disorders
Fundamentals of Genomic Editing
3. In Vitro Models of ASD: The Stem Cell Revolution
4. Animal Models in ASD Research
4.1. Rodents and the Modelling of Human Disorders
4.1.1. Mus Musculus in ASD Research
4.1.2. Rattus norvegicus in ASD Research
4.2. Zebrafish and the Modeling of Human Disorders
4.2.1. Zebrafish and Mammals: Conservation throughout Evolution
4.2.2. Gene Targeting in Zebrafish
4.2.3. Characterization of Zebrafish Models
4.2.4. Limitations of Zebrafish to Model Human Disorders
5. Future Challenges
5.1. In Vitro Modelling
5.2. In Vitro Modelling
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
ABA | Applied Behavior Analysis |
ADNP/Adnp | Activity dependent neuroprotector homeobox |
AFF2 | AF4/FMR2 family, member 2 |
ARHGEF9 | Cdc42 guanine nucleotide exchange factor 9 |
ARID1B/Arid1b/arid1b | AT-rich interaction domain 1B |
ARRIVE | Animals in Research: Reporting In Vivo Experiments |
ARX/arxa | Aristaless related homeobox |
ASD | Autism Spectrum Disorders |
ASH1L/Ash1l | ASH1 like histone lysine methyltransferase |
ASTN2 | Astrotactin 2 |
atoh1 | Atonal bHLH transcription factor 1 |
ath5 | Atonal bHLH transcription factor 7 |
ATRX | α thalassemia/mental retardation syndrome X-linked |
AUTS2/auts2a and auts2b | Autism susceptibility candidate 2 |
BCKDK/Bckdk | Branched chain ketoacid dehydrogenase kinase |
brn3c | POU class 4 homeobox 3 |
CACNA1C/Cacna1c/cacna1c | Calcium channel voltage-dependent, L type, α 1C subunit |
Cas | CRISPR-associated genes |
Cas13 | CRISPR-associated endoribonuclease Cas13 |
Cas9 | CRISPR associated endonuclease Cas9 |
CDKL5 | Cyclin-dependent kinase-like 5 |
CEP41/cep41 | Testis specific, 14 |
CHD2/Chd2/chd2 | Chromodomain helicase DNA binding protein 2 |
CHD8/Chd8/chd8 | Chromodomain helicase DNA binding protein 8 |
CIC/Cic | Capicua transcriptional repressor |
c-Myc | MYC proto-oncogene |
CNTN5 | Contactin 5 |
CNTNAP2/Cntnap2/cntnap2a and cntap2b | Contactin associated protein-like 2 |
CNVs | Copy Number Variations |
Cre | Cre recombinase |
crh | Corticotropin releasing hormone |
CRISPR | Clustered Regularly Interspaced Short Palindromic Repeats |
CRISPRa | CRISPR activation |
CRISPRi | CRISPR interference |
crRNA | CRISPR RNA |
CTNND2/ctnnd2b | Catenin (cadherin-associated protein), delta 2 |
CYFIP1/Cyfip1 | Cytoplasmic FMR1 interacting protein 1 |
D. rerio | Danio rerio |
dat | Dopamine transporter/Solute carrier family 6 member 3 |
dCas9 | Catalytically dead Cas9 |
Disc1 | Disrupted in schizophrenia 1 |
DNA | Deoxyribonucleic acid |
dpf | Days post-fertilization |
DSBs | Double-Strand Breaks |
DSM-5 | Diagnostic and statistical manual of mental disorders, 5th edition |
DYRK1A/dyrk1a | Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A |
EHMT1 | Euchromatic histone-lysine N-methyltransferase 1 |
elavl3 | ELAV like neuron-specific RNA binding protein 3 |
emx1 | Empty spiracles homeobox 1 |
En-1 | Engrailed homeobox 1 |
ENU | N-ethyl-N-nitrosourea |
Ext1 | Exostosin glycosyltransferase 1 |
FMR1/Fmr1/fmr1 | Fragile X mental retardation 1 |
FokI | Type IIS restriction endonuclease from Flavobacterium okeanokoites |
GABA | γ-aminobutyric acid |
GABRB3/Gabrb3 | γ-aminobutyric acid type A receptor, subunit beta3 |
gad1b | Glutamate decarboxylase 1b |
GFAP/gfap | Glial fibrillary acidic protein |
glyt2 | Sodium and chloride dependent glycine transporter 2 |
gsx1 | GS homeobox 1 |
GWAS | Genome-Wide Association Studies |
HDR | Homology-directed repair |
hiPSCs | Human induced pluripotent stem cells |
HNH | Endonuclease domain characterized by histidine and asparagine residues |
hpf | Hours post-fertilization |
Indel | Insertion and/or deletion |
isl1 | ISL LIM homeobox 1 |
KCNJ10/kcnj10 | Potassium voltage-gated channel subfamily J, member 10 |
KCNQ2 | Potassium voltage-gated channel subfamily Q, member 2 |
kctd15a | Potassium channel tetramerization domain containing 15a |
KDM6A/kdm6a | Lysine demethylase 6A |
KI | Knock-in |
Klf4 | Kruppel like factor 4 |
KO | Knockout |
lncRNA | Long non-coding RNA |
LOF | Loss of function |
M. musculus | Mus musculus |
MAPK | Mitogen-activated protein kinase |
MECP2/Mecp2/mecp2 | Methyl CpG binding protein 2 |
MET/met | Met proto-oncogene |
MGE | Medial ganglionic eminence |
mnx1 | Motor neuron and pancreas homeobox 1 |
MOs | Morpholinos |
mRNA | Messenger RNA |
mTORC1 | Mammalian target of rapamycin complex 1 |
MYT1L/mytl1a and mytl1b | Myelin transcription factor 1-like |
NBEA/nbea | Neurobeachin |
nCas9 | Cas9 nickase |
NDDs | Neurodevelopmental disorders |
neurod | Neurogenic differentiation factor 1 |
neurog1 | Neurogenin 1 |
NHEJ | Non-homologous end joining |
NLGN2/Nlgn2 | Neuroligin 2 |
NLGN3/Nlgn3 | Neuroligin 3 |
NMDARs | N-methyl-D-aspartate receptors |
NR3C2/nr3c2 | Nuclear receptor subfamily 3, group C, member 2 |
NRXN1/Nrxn1 | Neurexin 1 |
NS | Non specified |
Oct3/4 | Octamer binding transcription factor 3/4 |
olig2 | Oligodendrocyte lineage transcription factor 2 |
otx2a | Orthodenticle homeobox 2a |
OXTR/oxtr | Oxytocin receptor |
p53 | Tumor protein p53 |
PAM | Protospacer adjacent motif |
PCNA | Proliferating cell nuclear antigen |
PDD-NOS | Pervasive developmental disorder not otherwise specified |
pet1 | FEV transcription factor, |
PREPARE | Planning Research and Experimental Procedures on Animals: Recommendations for Excellence |
PRT | Pivotal Response Treatment |
PTCHD1 | Patched domain containing 1 |
PTCHD1-AS | PTCHD1 antisense RNA |
PTEN/Pten | Phosphatase and tensin homolog |
ptf1a | Pancreas associated transcription factor 1a |
R. norvegicus | Rattus norvegicus |
RELN/Reln/reln | Reelin |
RERE/rerea and rereb | Arginine-glutamic acid dipeptide repeats |
RNA | Ribonucleic acid |
RNA-seq | RNA sequencing |
RORα | Nuclear receptor ROR-α |
RuvC | Endonuclease domain involved in DNA repair |
SCN1A/Scn1a | Sodium channel, voltage-gated, type I, α subunit |
SCN2A/Scn2a | Sodium channel, voltage-gated, type II, α subunit |
SFARI | Simons Foundation Autism Research Initiative |
sgRNA | Single guide RNA |
SHANK2/Shank2 | SH3 and multiple ankyrin repeat domains 2 |
SHANK3/Shank3/shank3a and shankb | SH3 and multiple ankyrin repeat domains 3 |
shRNA | Short hairpin RNA |
Sox2/sox2-sox2 | SRY-box transcription factor 2 |
sox10 | SRY-box transcription factor 10 |
SVZ | Subventricular zone |
SYNGAP1/syngap1a and syngap1b | Synaptic Ras GTPase activating protein 1 |
TALENs | Transcription Activator–Like Effector Nucleases |
TALEs | Transcription Activator-Like Effectors |
TAOK2/Taok2 | TAO kinase 2 |
TBR1/Tbr1 | T-box brain transcription factor 1 |
tbx2b | T-box transcription factor 2b |
TCF4/Tcf4 | Transcription factor 4 |
th1 | Tyrosine hydroxylase 1 |
TILLING | Targeting Induced Local Lesions in Genomes |
tracrRNA | Trans-activating crRNA |
tRNA | Transfer ribonucleic acid |
TRPC6 | Transient receptor potential cation channel, subfamily C, member 6 |
TSC2/Tsc2 | Tuberous sclerosis 2 |
UBE3A/Ube3a | Ubiquitin protein ligase E3A |
UPF3B/Upf3b | UPF3B regulator of nonsense mediated mRNA decay |
USVs | Ultrasonic vocalizations |
vglut2.2 | Vesicular glutamate transporter 2.2 |
vglut2a | Vesicular glutamate transporter 2.1 |
vmat2 | Vesicular monoamine transporter 2 |
WES | Whole exome sequencing |
WGS | Whole genome sequencing |
ZFNs | Zinc Finger Nucleases |
ZNF804A | Zinc finger protein 804A |
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Clinical Diagnosis Criteria for ASD |
---|
Deficits in social communication and interaction |
Restricted and repetitive patterns of behavior, interests, or activities Symptoms present during early development Presence of impairments in important areas of an individual’s functioning Symptoms are not better explained by other mental disorder |
Type of Therapy | Therapy | Procedure | Areas with Improvement | Side Effects |
---|---|---|---|---|
Psychosocial therapies | Applied behavior analysis (ABA) | Repetition of learning trials (positive reinforcement) | Intellectual functioning, language, daily living skills and socialization | Long-term and costly therapy, need patient’s cooperation and motivation |
Pivotal Response Treatment (PRT) | Targets specific skills and motivations | Improve communication skills and less disruptive behaviors compared to ABA | No significant side effects | |
Parent-mediated early interventions | Interventions that can be applied at home by parents | Socialization and communication | No significant side effects | |
Social skills interventions | Interventions to improve social skills | Emotional regulation, communication and socialization | No significant side effects | |
Pharmacology | Risperidone | Atypical Antipsychotics | Irritability, socialization and communication | Weight gain, increased appetite and somnolence |
Aripiprazole | Atypical Antipsychotics | Irritability | Weight gain and somnolence | |
Olanzapine | Atypical Antipsychotics | Irritability | Weight gain | |
Ziprasidone | Atypical Antipsychotics | Irritability | Cardiovascular alterations and somnolence | |
Paliperidone | Atypical Antipsychotics | Irritability | Weight gain and extrapyramidal symptoms | |
Haloperidol | Typical Antipsychotics | Hyperactivity, stereotypical behaviors and learning on discrimination tasks | Somnolence, irritability and dystonic reactions | |
Antidepressants: venlafaxine | Typical Antipsychotics | Repetitive behaviors, socialization and communication | Hyperactivity, inattention, nausea and polyuria | |
Antidepressants: clomipramine | Typical Antipsychotics | Stereotypical behavior and anger management | No significant side effects | |
Divalproex sodium | Mood stabilizers | Irritability and repetitive behaviors | No significant side effects | |
Methylphenidate | Stimulants/atomoxetine/α-2 agonists | Hyperactivity | Appetite decrease, insomnia, irritability and emotional outbursts | |
Atomoxetine | Stimulants/atomoxetine/α-2 agonists | Hyperactivity and impulsivity | No significant side effects | |
α-2 agonists: clonidine and guanfacine | Stimulants/atomoxetine/α-2 agonists | Hyperactivity | Somnolence | |
Naltrexone | Other medications | Hyperactivity and impulsivity | No significant side effects | |
Complementary alternative medicine | Melatonin | Sleep disturbances | No significant side effects |
Cell Lines Derived from hiPSCs | ASD-Associated Gene | Alterations Due to the Lack of Expression of ASD-Associated Gene | References |
---|---|---|---|
Cortical neurons | EHMT1 | Reduced neurite length and complexity Altered neuronal activity Increased expression of proliferation genes Decreased expression of maturation and migration genes | [64] |
MECP2 | Increased synaptogenesis and dendritic complexity Altered neuronal network synchronization | [65] | |
NRXN1 | Altered ion transport and calcium signaling | [66] | |
PTCHD1 | Decreased frequency of miniature excitatory postsynaptic currents N-methyl-D-aspartate receptor (NMDARs) hypofunction | [61] | |
PTCHD1-AS | Decreased frequency of miniature excitatory postsynaptic currents | [61] | |
SHANK2 | Increased number of synapses, dendritic length and complexity Increased frequency of spontaneous excitatory postsynaptic currents Altered expression of genes associated to neuronal morphogenesis, plasticity and synapse | [67] | |
SHANK3 | Synaptic alteration and decreased dendritic spines | [68,69] | |
TSC2 | Mitochondria disorganization and altered mitophagy Increased soma size and neurite number mTORC1 signaling pathway hyperactivation Increased neuronal activity and upregulation of cell adhesion genes | [70,71] | |
Dopaminergic neurons | RELN | Altered neuronal migration | [72] |
Glutamatergic neurons | AFF2 | Alteration in genes associated with neuronal development Decreased synaptic activity: reduced spontaneous excitatory postsynaptic currents | [73] |
ASTN2 | Alteration in genes associated with neuronal development Decreased synaptic activity: reduced spontaneous excitatory postsynaptic currents | [73] | |
ATRX | Alteration in genes associated with neuronal development Decreased synaptic activity: reduced spontaneous excitatory postsynaptic currents | [73] | |
CNTN5 | Increased neuronal activity | [74] | |
KCNQ2 | Decreased synaptic activity: reduced spontaneous excitatory postsynaptic currents | [73] | |
SCN2A | Alteration in genes associated with morphogenesis Decreased synaptic activity: reduced spontaneous excitatory postsynaptic currents | [73] | |
Neuron-like cells | ARHGEF9 | Altered mTORC1 signaling pathway | [75] |
CACNA1C | Altered calcium signaling Altered differentiation of neurons from cortical layers Increased production of norepinephrine and dopamine Altered expression of tyrosine hydrolase | [76,77] | |
CDKL5 | Alterations in neuronal activity | [78] | |
CHD8 | Altered expression of genes associated with neural development, β-catenin/Wnt signaling, extracellular matrix and skeletal system development | [79] | |
COSMOC | Impaired redox homeostasis Altered PTBP2 splicing | [62] | |
FMR1 | Altered DNA methylation patterns Altered expression of genes associated with neuronal development, migration and maturation Altered neurite formation and neuronal differentiation | [80,81,82] | |
SHANK3 | Alterations in the soma and neurites, as well as alterations in synaptic transmission Altered expression of genes associated to motility and neurogenesis | [83,84] | |
TRPC6 | Reduce neurite length and complexity Altered glutamatergic synapse formation and reduced sodium influx | [85] | |
Neural organoids | CHD8 | Alterations in the expression of gens associated with neurogenesis, β-catenin/Wnt signaling, neuronal differentiation and axonal guidance | [86] |
Neural progenitor cells | NRXN1 RELN | Alterations in neuronal adhesion and differentiation Overactivation of mTORC1 pathway | [87,88] [89] |
TRPC6 | Altered calcium signaling and expression of genes involved in cell adhesion and neurite formation | [85] | |
ZNF804A | Altered expression of pathways mediated by interferon-α 2 | [90] | |
Olfactory placodal neurons | SHANK3 | Decreased number of synapses Alterations during neural development in the soma and neurites | [91] |
Purkinje cells | TSC2 | Hypoexcitability and synaptic dysfunction mTORC1 pathway hyperactivation Altered neuronal differentiation | [92] |
Areas of Interest | Behavioral Assays in Rodents | Behavioral Assays in Zebrafish |
---|---|---|
Socialization |
|
|
Non-social patterns of behavior |
|
|
Communication |
|
|
ASD-Associated Gene/Mus musculus | Gene Modification Technique | Main Phenotypical Observations | Reference |
---|---|---|---|
ADNP/Adnp | KO by homologous recombination | Embryonic lethality (KO) Developmental delay Decreased neuronal survival Social and memory impairments | [101,102,103] |
ARID1B/Arid1b | KO by CRISPR/Cas9 Conditional heterozygous KO by Cas9 (floxed allele) | Increased lethality Abnormal brain and heart development Decreased neuronal precursor proliferation and cortical thickness Anxiety and social interaction alterations Decreased cognitive flexibility | [104,105] |
ASH1L/Ash1l | KO with gene trap vector, piggyBac or CRISPR/Cas9 | Increased lethality and infertility Delayed eye development Reduced adiposity Altered immune response Reduced chromatin modification | [106,107,108] |
CHD2/Chd2 | Targeted KO with cassette Cre-flox Conditional LOF in interneurons | Growth delay and increased mortality Abnormal synaptic transmission Reduced number of neural precursors and interneurons Altered hippocampal morphology Decreased object recognition memory Decreased spatial working memory | [109,110] |
CHD8/Chd8 | Knockdown (shRNAs) KO by CRISPR/Cas9 or Cre-LoxP | Altered brain development, corticogenesis and differentiation of neural precursors Reduced density of the dendritic tree Decreased myelination Increased anxiety and altered sociability Increased repetitive behaviors Altered memory patterns | [111,112,113,114,115,116,117,118] |
CIC/Cic | Conditional LOF in the neocortex, hippocampus and pallium | Altered hippocampal and cortical morphology Reduced number of postmitotic excitatory neurons of the forebrain Reduced dendritic complexity Reduced social interactions | [119] |
CNTNAP2/Cntnap2 | Targeted KO by gene replacement | Delayed growth Cortical disorganization in the brain Decreased levels of neuroreceptors Repetitive behaviors and seizures Impairments in social interactions | [120,121,122,123,124,125] |
GABRB3/Gabrb3 | Conditional LOF in endothelial cells Targeted KO | Altered brain morphology Reduced number of interneurons Reduced neuronal migration Decreased levels of GABA neurotransmitter Increased seizures, anxiety and depression Reduced social and tactile memory | [126,127,128,129,130] |
PTEN/Pten | Conditional LOF in: forebrain gabaergic and dopaminergic neurons; secondary progenitors in the subpallium SVZ; Purkinje cells; dentate gyrus, hippocampus, cortex or ventricular zone of the MGE | Increased lethality Altered brain morphology Reduced number of interneurons Increased neuronal size and connectivity Impaired neuronal differentiation Altered synaptic function Increased apoptosis in brain cells Increased thickness in the cerebellum Decreased number of Purkinje cells Reduced coordination Reduced social memory | [131,132,133,134,135,136,137] |
RELN/Reln | Spontaneous mutation | Altered morphology of the brain, cerebellum, cortex and olfactory bulb Reduced number of Purkinje cells Altered neuronal migration patterns Altered metabolism of neurotransmitters Impaired coordination Increased anxiety response levels | [138,139,140] |
SCN2A/Scn2a | Targeted KO by gene interruption Conditional LOF in dorsal telencephalic excitatory neurons | Increased apoptosis and mortality Seizures and hyperactivity Increased rearing Reduced anxiety responses | [141,142,143] |
SHANK2/Shank2 | Conditional LOF in Purkinje cells Targeted KO | Altered synaptic currents Increased anxiety and hyperactivity Reduced coordination Increased repetitive behaviors Reduced social approach Decreased spatial learning and memory | [144,145,146,147,148] |
TAOK2/Taok2 | Targeted KO by Cre-LoxP | Abnormal brain morphology and spine density Reduced dendritic length and complexity Reduced cortical lamination and thickness Impaired memory of context | [149] |
TBR1/Tbr1 | Conditional LOF in neurons of cortical layer 6 and subplate Targeted KO by homologous recombination | Altered brain morphology Reduced neuronal connectivity Reduced number of interneurons Altered differentiation of brain cells Altered cortical organization Altered synaptic currents Increased anxiety aggressiveness Increased aggressive | [146,150,151,152,153] |
UPF3B/Upf3b | Targeted KO by gene trap | Reduced spine density Altered morphology of cortical neurons Poor differentiation of neural progenitors Impaired sensorimotor gating Abnormal clasping reflex Abnormal sleep pattern Impaired startle response to acoustic stimuli | [154] |
ASD-Associated Gene/Rattus norvegicus | Gene Modification Technique | Main Phenotypical Observations | Reference |
---|---|---|---|
BCKDK/Bckdk | KO by spontaneous mutation | Neuronal alterations Reduced protein phosphorylation Infertility Altered development | [155] |
CACNA1C/Cacna1c | KO by ZFN | Altered social behavior and reduced USVs Increased perseverative behaviors | [156,157] |
CNTNAP2/Cntnap2 | KO by ZFN | Seizures Hyperactivity Altered audition and sleep routines | [158,159] |
CYFIP1/Cyfip1 | KO by CRISPR/Cas9 | Neuronal alterations Altered behavioral flexibility in learning tasks | [160] |
FMR1/Fmr1 | KO by ZFN | Increased repetitive behaviors and social alterations. Altered sensorimotor gating Memory difficulties Neuronal alterations Altered auditory responses | [161,162,163] |
MECP2/Mecp2 | KO by ZFN | High mortality Malocclusion Neuronal alterations Hypoactivity Altered social interaction and speech responses. Memory alterations Decreased grip strength | [164,165] |
NLGN2/Nlgn2 | Overexpression in the hippocampus | Decreased response to new stimuli and aggressive behavior | [166] |
NLGN3/Nlgn3 | KO by ZFN | Increased repetitive behaviors Hyperactivity and altered sleep routines Decreased body weight Altered juvenile play behavior and startle response Altered sensorimotor gating | [162,167] |
NRXN1/Nrxn1 | KO by biallelic deletion | Hyperactivity Altered startle response Memory alterations | [168] |
PTEN/Pten | Heterozygous KO by ZFN | Neuronal alterations | [169] |
SCN1A/Scn1a | KO by ENU mutagenesis | Increased repetitive behaviors Hyperactivity and anxiety Learning and memory difficulties Motor alterations Reduced dopamine levels | [170] |
SHANK2/Shank2 | KO by ZFN | Alterations in social behavior Hyperactivity and increased repetitive behavior Memory alterations Neuronal alterations | [171] |
SHANK3/Shank3 | KO by ZFN | Alterations in social behavior Neuronal alterations | [172] |
TCF4/Tcf4 | KO by CRISPR/Cas9 and knockdown by shRNA in the prefrontal cortex | Altered electrophysiological properties in neurons | [173] |
TSC2/Tsc2 | KO by spontaneous mutation | Enhanced episodic-like memory Enhanced seizure-induced plasticity Increased induction of phospho-p42-MAPK in the hippocampus Increased basal oxygen consumption in the brain | [174,175] |
UBE3A/Ube3a | KO by CRISPR/Cas9 | Motor, learning and memory difficulties | [176] |
ASD-Linked Gene/Danio rerio | Gene Modification Technique | Main Phenotypical Observations | Reference |
---|---|---|---|
ARID1B/arid1b | Knockdown by MOs | Reduced body length Altered expression of chondrogenic/osteogenic genes | [219] |
ARX/arxa | Knockdown by MOs | Altered brain development Neuronal alterations | [220] |
AUTS2/auts2a and auts2b | Knockdown by MOs | Microcephaly Altered jaw development Motor alterations Neuronal alterations | [221] |
CACNA1C/cacna1c | Knockdown by MOs | Cardiac alterations Altered jaw development | [222] |
CEP41/cep41 | Knockdown by MOs | Neuronal alterations Social behavior alterations | [223] |
CHD2/chd2 | Knockdown by MOs | Altered development Microcephaly, abnormal body curvature Swim bladder absence Motor difficulties | [224] |
CHD8/chd8 | Knockout by CRISPR/Cas9 and knockdown by MOs | Macrocephaly Reduction in post-mitotic enteric neurons | [225,226] |
CNTNAP2/cntnap2a and cntap2b | Knockout by ZFN | Altered development Microcephaly Neuronal alterations Motor alterations | [36] |
CTNND2/ctnnd2b | Knockdown by MOs | Reduced body length Notochord alterations | [227] |
DYRK1A/dyrk1a | Knockout by TALENs | Altered response to social stimuli | [228] |
FMR/fmr1 | Knockout by ENU-mutagenesis and CRISPR/Cas9 | Altered cephalic development Hyperactivity Increased anxiety Altered social behavior Learning difficulties | [229,230,231] |
KCNJ10/kcnj10 | Knockdown by MOs | Motor alterations Altered development | [232] |
KDM6A/kdm6a | Knockdown by MOs | Reduced body length Altered development Notochord alterations Neuronal alterations | [233,234] |
MECP2/mecp2 | Knockout by ENU-mutagenesis and knockdown by MOs | Altered immune response Neuronal alterations | [235,236,237] |
MET/met | Knockdown by MOs | High mortality Neuronal alterations | [238] |
MYT1L/mytl1a and mytl1b | Knockdown by MOs | Reduced levels of oxytocin | [239] |
NBEA/nbea | Knockout by ENU-mutagenesis and TALENs | Neuronal alterations Altered response to startle stimuli | [240] |
NR3C2/nr3c2 | Knockout by CRISPR/Cas9 | Altered social behavior Altered sleep routines | [241] |
OXTR/oxtr | Knockout by TALENs | Altered oxytocin signaling pathway Memory alterations in social and non-social recognition | [242] |
RELN/reln | Knockout by TALENs | Altered social behavior Altered serotonin signaling pathway | [243] |
RERE/rerea and rereb | Knockout by ENU-mutagenesis | Altered startle response to stimuli Vision and hearing difficulties | [244] |
SHANK3/shank3a and shankb | Knockout by CRISPR/Cas9 | Altered development Neuronal alterations Reduced social behavior, hypoactivity | [245,246] |
SYNGAP1/syngap1a and syngap1b | Knockdown by MOs | Delayed development High mortality Neuronal alterations Motor difficulties | [245] |
Transgenic Line | Expression Pattern | Reference |
---|---|---|
ath5:GFP | Retinal ganglion cells | [247] |
brn3c:GFP | Retinal ganglion cells | [248] |
dat:EGFP | Dopaminergic neurons | [249] |
elavl3:lynTagRFP | Post-mitotic neurons | [250] |
En-1:GFP | Circumferential ascending interneurons | [251] |
flk1:GFP | Endothelial cells | [252] |
gad1b:RFP | Gabaergic neurons | [253] |
gfap:GFP | Radial glial cells | [254] |
glyt2:GFP | Glycinergic neurons | [255] |
gsx1:GFP | Gabaergic neurons | [253] |
isl1:GFP | Cranial motor neurons | [256] |
kctd15a:GFP | Torus lateralis | [257] |
mnx1:GFP | Motor neurons | [258] |
neurod:EGFP | Immature neurons | [259] |
neurog1:GFP | Primary neurons | [260] |
olig2:EGFP | Oligodendrocytes | [261] |
pet1:GFP | Serotonergic neurons | [262] |
qrfp:GFP | Rostral hipothalamus | [263] |
sox10:GFP | Neural crest cells/Neurocranium cartilague | [264] |
tbx2b:EGFP | Cone photoreceptor cells | [265] |
Vglut2a:GFP | Glutamatergic neurons | [253] |
vmat2:GFP | Monoaminergic neurons | [266] |
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Pensado-López, A.; Veiga-Rúa, S.; Carracedo, Á.; Allegue, C.; Sánchez, L. Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish. Genes 2020, 11, 1376. https://doi.org/10.3390/genes11111376
Pensado-López A, Veiga-Rúa S, Carracedo Á, Allegue C, Sánchez L. Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish. Genes. 2020; 11(11):1376. https://doi.org/10.3390/genes11111376
Chicago/Turabian StylePensado-López, Alba, Sara Veiga-Rúa, Ángel Carracedo, Catarina Allegue, and Laura Sánchez. 2020. "Experimental Models to Study Autism Spectrum Disorders: hiPSCs, Rodents and Zebrafish" Genes 11, no. 11: 1376. https://doi.org/10.3390/genes11111376