Neurodevelopmental Abnormalities Research Articles

DHA Improves neurodevelopmental abnormalities in offspring of gestational diabetes mellitus patients via the PPAR-γ/FATP4 pathway.

Offspring of women with gestational diabetes mellitus (GDM) face an increased risk of long-term neurodevelopmental abnormalities. This study explores the altered expression of key placental fatty acid transport proteins-FATP2, FATP4, FATP6, FABP4, and FAT/CD36-in GDM patients, and the potential of docosahexaenoic acid (DHA) to mitigate neurodevelopmental risks in offspring by enhancing their expression through activation of peroxisome proliferator-activated receptor γ (PPAR-γ). Our findings demonstrate that placental FATP4 expression is reduced in GDM patients. In HTR8/SVneo cells, PPAR-γ activation upregulated the expression of FATP4, FAT/CD36, and FABP4, while PPAR-γ inhibition only reduced FAT/CD36 expression. DHA treatment led to increased expression of FATP4, FATP/CD36 and FABP4, which was partially reversed by PPAR-γ inhibition. Consistent results were observed in an insulin-resistant cell model. Supplementing GDM mice with exogenous DHA restored placental FATP4 expression and improved offspring social behavior and cognitive function. These results suggest that DHA supplementation during pregnancy could reduce the adverse effects of GDM on placental FATP4 expression and support better neurodevelopmental outcomes in offspring by promoting essential fatty acid transport through the PPAR-γ/FATP4 pathway. This study highlights the therapeutic potential of DHA in improving fetal outcomes in GDM pregnancies.

Memory Decline and Aberration of Synaptic Proteins in X-Linked Moesin Knockout Male Mice

Objective This study aims to investigate may moesin deficiency resulted in neurodevelopmental abnormalities caused by negative impact on synaptic signaling ultimately leading to synaptic structure and plasticity.Methods Behavioral assessments measured neurodevelopment (surface righting, negative geotaxis, cliff avoidance), anxiety (open field test, elevated plus maze test), and memory (passive avoidance test, Y-maze test) in moesin-knockout mice (KO) compared to wild-type mice (WT). Whole exome sequencing (WES) of brain (KO vs. WT) and analysis of synaptic proteins were performed to determine the disruption of signal pathways downstream of moesin. Risperidone, a therapeutic agent, was utilized to reverse the neurodevelopmental aberrance in moesin KO.Results Moesin-KO pups exhibited decrease in the surface righting ability on postnatal day 7 (p<0.05) and increase in time spent in the closed arms (p<0.01), showing increased anxiety-like behavior. WES revealed mutations in pathway aberration in neuron projection, actin filament-based processes, and neuronal migration in KO. Decreased cell viability (p<0.001) and expression of soluble NSF adapter protein 25 (SNAP25) (p<0.001) and postsynaptic density protein 95 (PSD95) (p<0.01) was observed in days in vitro 7 neurons. Downregulation of synaptic proteins, and altered phosphorylation levels of Synapsin I, mammalian uncoordinated 18 (MUNC18), extracellular signal-regulated kinase (ERK), and cAMP response element-binding protein (CREB) was observed in KO cortex and hippocampus. Risperidone reversed the memory impairment in the passive avoidance test and the spontaneous alternation percentage in the Y maze test. Risperidone also restored the reduced expression of PSD95 (p<0.01) and the phosphorylation of Synapsin at Ser605 (p<0.05) and Ser549 (p<0.001) in the cortex of moesin-KO.Conclusion Moesin deficiency leads to neurodevelopmental delay and memory decline, which may be caused through altered regulation in synaptic proteins and function.

Polycomb-associated and Trithorax-associated developmental conditions-phenotypic convergence and heterogeneity.

Polycomb group (PcG) and Trithorax group (TrxG) complexes represent two major components of the epigenetic machinery. This study aimed to delineate phenotypic similarities and differences across developmental conditions arising from rare variants in PcG and TrxG genes, using data-driven approaches. 462 patients with a PcG or TrxG-associated condition were identified in the DECIPHER dataset. We analysed Human Phenotype Ontology (HPO) data to identify phenotypes enriched in this group, in comparison to other monogenic conditions within DECIPHER. We then assessed phenotypic relationships between single gene diagnoses within the PcG and TrxG group, by applying semantic similarity analysis and hierarchical clustering. Finally, we analysed patient-level phenotypic heterogeneity in this group, irrespective of specific genetic diagnosis, by applying the same clustering approach. Collectively, PcG/TrxG diagnoses were associated with increased reporting of HPO terms relating to integument, growth, head and neck, limb and digestive abnormalities. Gene group analysis identified three multi-gene clusters differentiated by microcephaly, limb/digit dysmorphologies, growth abnormalities and atypical behavioural phenotypes. Patient-level analysis identified two large clusters differentiated by neurodevelopmental abnormalities and facial dysmorphologies respectively, as well as smaller clusters associated with more specific phenotypes including behavioural characteristics, eye abnormalities, growth abnormalities and skull dysmorphologies. Importantly, patient-level phenotypic clusters did not align with genetic diagnoses. Data-driven approaches can highlight pathway-level and gene-level phenotypic convergences, and individual-level phenotypic heterogeneities. Future studies are needed to understand the multi-level mechanisms contributing to both convergence and variability within this population, and to extend data collection and analyses to later-emerging health characteristics.

Development of a TaqMan-based dosage analysis PCR assay for the molecular diagnosis of 22q11.2 deletion syndrome.

A 1.5 to 3 Mb microdeletion of chromosome 22q11.2 with loss of multiple genes including histone cell cycle regulator (HIRA) causes 22q11.2 deletion syndrome (22q11.2 DS), a common disorder with variable manifestations including congenital malformations affecting the heart, palate and kidneys in association with neurodevelopmental, psychiatric, endocrine and autoimmune abnormalities. The aim of this study was to develop a TaqMan based dosage analysis PCR (TaqMan qPCR) for use as a rapid, cost-effective test for clinically suspected patients fulfilling previously described criteria for molecular diagnosis of 22q11.2 DS in a lower middle-income country where the cost of testing limits its use in routine clinical practice. Nineteen patients were recruited with informed consent following ethical approval from the Ethics Review Committee (ERC), Lady Ridgway hospital, Colombo. Dosage analysis of extracted DNA was performed using a TaqMan qPCR assay by amplifying regions within the target (HIRA) and control [Testin LIM domain protein (TES)] genes of a suspected patient (P) and unaffected person (N). For detection of a deletion, the normalized values (HIRA / TES dosage) of a patient were compared with normalized values of an unaffected person. A ratio of P:N of 0.5 confirmed presence of a deletion while a ratio of 1.0 refuted this. Seven of 19 (37%) cases were confirmed to have a HIRA deletion, confirming the diagnosis of 22q11.2 DS, with these results being in complete agreement with those of fluorescence in-situ hybridization (FISH), (performed in 9/19 (47.3%) of recruited cases) and whole exome sequencing (WES) (all 19 samples tested). This TaqMan qPCR assay was able to reliably distinguish HIRA deleted cases from the non-deleted ones. The assay was both less expensive and faster compared to commercially available alternatives in our setting, including FISH and multiple ligation-dependent probe amplification (MLPA).

Dysregulation of REST and its target genes impacts the fate of neural progenitor cells in down syndrome

Increasing shreds of evidence suggest that neurogenic-to-gliogenic shift may be critical to the abnormal neurodevelopment observed in individuals with Down syndrome (DS). REST, the Repressor Element-1 Silencing Transcription factor, regulates the differentiation and development of neural cells. Downregulation of REST may lead to defects in post-differentiation neuronal morphology in the brain of the DS fetal. This study aims to elucidate the role of REST in DS-derived NPCs using bioinformatics analyses and laboratory validations. We identified and validated vital REST-targeted DEGs: CD44, TGFB1, FN1, ITGB1, and COL1A1. Interestingly, these genes are involved in neurogenesis and gliogenesis in DS-derived NPCs. Furthermore, we identified nuclear REST loss and the neuroblast marker, DCX, was downregulated in DS human trisomic induced pluripotent stem cells (hiPSCs)-derived NPCs, whereas the glioblast marker, NFIA, was upregulated. Our findings indicate that the loss of REST is critical in the neurogenic-to-gliogenic shift observed in DS-derived NPCs. REST and its target genes may collectively regulate the NPC phenotype.

Missense variants at the p.Arg225 residue in ARHGEF40 identified in individuals with multiple congenital anomalies and developmental delay.

The ARHGEF40 gene, also known as SOLO, encodes a RhoA-targeting guanine nucleotide exchange factor (GEF) and is currently considered a candidate gene with a potential relationship to disease. Our laboratory has confirmed variants at position p.Arg225 of the ARHGEF40 protein in multiple unrelated individuals with a phenotype including dysmorphic features, congenital anomalies and neurodevelopmental abnormalities. Here, we provide genetic and phenotypic information for two individuals harboring de novo variants at p.Arg225 and sharing a highly similar phenotype. This report suggests a relationship between variants at this amino acid position and autosomal dominant disease, and further studies will be needed to characterize this disease-gene relationship and elucidate the disease mechanism.

Nanoplastic-Induced Developmental Toxicity in Ascidians: Comparative Analysis of Chorionated and Dechorionated Phallusia mammillata Embryos.

Nanoplastics pose a growing threat to marine ecosystems, particularly affecting the early developmental stages of marine organisms. This study investigates the effects of amino-modified polystyrene nanoparticles (PS-NH2, 50 nm) on the embryonic development of Phallusia mammillata, a model ascidian species. Both chorionated and dechorionated embryos were exposed to increasing concentrations of PS-NH2 so morphological alterations could be assessed with a high-content analysis of the phenotypes and genotoxicity. PS-NH2 induced the same morphological alterations in both chorionated and dechorionated embryos, with dechorionated embryos being more sensitive (EC50 = 3.0 μg mL-1) than chorionated ones (EC50 = 6.26 μg mL-1). Interestingly, results from the morphological analysis showed two concentration-dependent mechanisms of action: (i) at concentrations near the EC50, neurodevelopmental abnormalities resembling the ones induced by exposure to known endocrine disruptors (EDs) were observed, and (ii) at higher concentrations (15 μg mL-1 and 7.5 μg mL-1 for chorionated and dechorionated embryos, respectively), a nonspecific toxicity was evident, likely due to general oxidative stress. The phenotypes resulting from the PS-NH2 treatment were not related to DNA damage, as revealed by a genotoxicity assay performed on neurula embryos. Our data suggest that PS-NH2-induced toxicity is primarily mediated through oxidative stress, probably triggered by interactions between the positive charges of the PS NPs and the negative charges on the cell membranes. The lack of a protective chorion further exacerbated these effects, highlighting its role in mitigating/protecting against NP-induced damage.

Interactions of the Pneumococcus with the Central Nervous System: Postnatal Meningitis Versus Fetal Neurodevelopment.

In young children, pneumococcal meningitis epitomizes the paradigm of a destructive innate inflammatory response in the central nervous system: a five-alarm fire. In contrast, cell-free bacterial components reaching the fetal brain from an infected mother signal a quiet, noninflammatory immune response that drives abnormal neurodevelopment, changing brain architecture through neuroproliferation. This review addresses the difference between prenatal and postnatal bacterial-host signaling within the brain.

The impact of clinical seizures and adverse brain MRI patterns in neonates with hypoxic-ischemic encephalopathy and abnormal neurodevelopment

This study aimed to investigate the associations among seizures, clinical characteristics, and brain injury on Magnetic Resonance Imaging (MRI) in infants with Hypoxic Ischemic Encephalopathy (HIE), and to determine whether these findings can predict unfavorable neurodevelopmental outcomes. Clinical and electrographic seizures were assessed by amplitude-integrated electroencephalogram, and the extent of brain injury was evaluated by using MRI. At 12‒24 months of age, developmental impairment or death was assessed. Between 2012 and 2020, 143 newborns were admitted for HIE, and 8 infants were excluded from the study. Eighty-five infants were diagnosed with greater than moderate HIE and 65 infants underwent therapeutic hypothermia. In addition, 38 infants experienced clinical seizures (clinical seizure group, CSG), 49 infants had electrographic seizures (Electrographic Seizure Group, ESG), and 48 infants had no seizures (no seizure group, NSG). The proportion of infants with neurodevelopmental impairment or death was significantly higher in the CSG than in the NSG (57.7 % and 26.1 %, p = 0.026). A risk factor analysis indicated that cord blood pH (adjusted Odds Ratio [aOR = 0.01]; 95 % Confidence Interval [95 % CI 0.001‒0.38]; p = 0.015) and MRI findings (aOR = 4.37; 95 % CI 1.25‒15.30; p = 0.012) were independently associated with abnormal neurodevelopment, after adjustment. Clinical seizures in infants with HIE were independently associated with abnormal neurodevelopment. However, cord blood pH and abnormal brain MRI findings were consistently linked to long-term neurodevelopmental outcomes.

Neurodevelopmental Abnormalities in Down Syndrome: Assessing Structural and Functional Deficits.

Down syndrome (DS) is a genetic intellectual disorder caused by trisomy of chromosome 21 (Hsa21) and presents with a variety of phenotypes. The correlation between the chromosomal abnormality and the resulting symptoms is unclear, partly due to the spectrum of impairments observed. However, it has been determined that trisomy 21 contributes to neurodegeneration and impaired neurodevelopment resulting from decreased neurotransmission, neurogenesis, and synaptic plasticity. DS is linked to synaptic abnormalities and hindered hippocampal neuron development as well. Altered synaptic plasticity in the hippocampus decreases long-term potentiation, leading to short- and long-term learning and memory deficits. Individuals with DS show reduced gray matter, which affects cerebral cortex structure and impairs coordination and thought. Neurotransmitter excess, such as increased gamma-aminobutyric acid (GABA) release, causes over-inhibition and contributes to cognitive deficits. This inhibition also affects hippocampal synaptic plasticity. Additionally, DS often involves neurodegeneration of cholinergic neurons in the basal forebrain, further impairing learning and memory. Reduced glutamate transmission and decreased amyloid precursor protein metabolism contribute to synaptic plasticity deficits and behavioral changes in DS. Decreased neurotransmission, diminished motor neurons, and impaired cerebellar and cerebral development are the main causes of motor deficits in DS. This review discusses the stark structural changes in DS and their functional consequences.

Clinical characteristics and genetic analysis of four pediatric patients with Kleefstra syndrome

BackgroundKleefstra syndrome spectrum (KLEFS) is an autosomal dominant disorder that can lead to intellectual disability and autism spectrum disorders. KLEFS encompasses Kleefstra syndrome-1 (KLEFS1) and Kleefstra syndrome-2 (KLEFS2), with KLEFS1 accounting for more than 75%. However, limited information is available regarding KLEFS2. KLEFS1 is caused by a subtelomeric chromosomal abnormality resulting in either deletion at the end of the long arm of chromosome 9, which contains the EHMT1 gene, or by variants in the EHMT1 gene and the KMT2C gene that cause KLEFS2.MethodsThis study was a retrospective analysis of clinical data from four patients with KLEFS. Exome sequencing (ES) and Sanger sequencing techniques were used to identify and validate the candidate variants, facilitating the analysis of genotype‒phenotype correlations of the EHMT1 and KMT2C genes. Protein structure modeling was performed to evaluate the effects of the variants on the protein’s three-dimensional structure. In addition, real-time quantitative reverse transcription‒polymerase chain reaction (RT‒qPCR) and western blotting were used to examine the protein and mRNA levels of the KMT2C gene.ResultsTwo patients with KLEFS1 were identified: one with a novel variant (c.2382 + 1G > T) and the other with a previously reported variant (c.2426 C > T, p.Pro809Leu) in the EHMT1 gene. A De novo deletion at the end of the long arm of chromosome 9 was also reported. Furthermore, a patient with KLEFS2 was identified with a novel variant in the KMT2C gene (c.568 C > T, p.Arg190Ter). The RT‒qPCR and western blot results revealed that the expression of the KMT2C gene was downregulated in the KLEFS2 sample.ConclusionThis study contributes to the understanding of both KLEFS1 and KLEFS2 by identifying novel variants in EHMT1 and KMT2C genes, thereby expanding the variant spectrum. Additionally, we provide the first evidence of how a KMT2C variant leads to decreased gene and protein expression, enhancing our understanding of the molecular mechanisms underlying KLEFS2. Based on these findings, children exhibiting developmental delay, hypotonia, distinctive facial features, and other neurodevelopmental abnormalities should be considered for ES to ensure early intervention and treatment.

Gross anatomical features of the insular cortex in affective disorders

IntroductionThe number of insular gyri is elevated in patients with schizophrenia. Thus, it has potential as a marker of early neurodevelopmental abnormalities. However, currently it remains unclear whether patients with other neuropsychiatric disorders, such as affective disorders, also have this gross brain anatomical feature.Materials and methodsThe macroscopic features of the insular cortex in 26 patients with bipolar disorder (BD), 56 with major depressive disorder (MDD), and control subjects for each clinical group (24 for BD and 33 for MDD) were assessed using magnetic resonance imaging.ResultsThe number of short insular gyri was higher in BD patients than in matched controls bilaterally with well-developed accessory and middle short gyri. Furthermore, the left middle short gyrus was more developed in MDD patients than in matched controls, and was weakly associated with the severity of depressive symptoms.DiscussionThe present results indicate that changes in the gross morphology of the insular cortex in BD and MDD is a potential vulnerability factor associated with their neurodevelopmental pathologies, and may also contribute to the severity of symptoms in MDD.

Investigating the Impact of Chronical Prenatal Alcohol Exposure on Fetal Vascular Development Across Pregnancy Stages Using Photoacoustic Tomography.

Prenatal alcohol exposure (PAE) is a major contributor to fetal alcohol spectrum disorder (FASD), resulting in neurodevelopmental abnormalities. This study utilizes photoacoustic tomography (PAT) to investigate the effects of PAE on fetal brain vasculature in mice. PAT imaging was conducted from embryonic Day 10 (E10) to Day 20 (E20), aimed to compare two alcohol-exposed groups with a control group. Key vascular parameters, including blood vessel diameter and density, and oxygen saturation (sO2), were analyzed. Results show significant reductions in vessel size and density, as well as reduced sO2 levels, in alcohol-exposed groups, especially from E14 onward, compared to controls. These findings underscore the vulnerability of the fetal brain to alcohol exposure during early development and highlight the potential of PAT as a valuable tool for investigating FASD-related vascular changes.

Ubiquitination-deficit of Cnot4 impairs the capacity of proliferation and differentiation in mouse embryonic stem cells.

Neurodevelopmental abnormalities are significant contributors to a variety of neurological disorders. Ubiquitination is essential for embryonic development and plays a pivotal role in neurodevelopment. Although Cnot4 possesses E3-ubiquitin ligase activity, its function in neurodevelopment and embryonic stem cells (ESCs) remains inadequately understood. This study examined the impact of Cnot4 ubiquitination-deficit in mouse ESCs using flow cytometry, CCK-8 assays, immunofluorescence, western blotting, RNA sequencing (RNA-seq), and intracellular Ca2+ measurement. Findings demonstrated that the lack of ubiquitination in Cnot4 reduced ESC proliferation rates and facilitated ectodermal differentiation during spontaneous ESC differentiation. RNA-seq analysis identified that the differentially expressed genes were primarily linked to glucose metabolism and Ca2+ signaling pathways. Additionally, results indicated that the ubiquitination-deficit in Cnot4 caused increased intracellular Ca2+ levels in mESCs. These findings suggest that Cnot4 plays a critical role in the regulation of proliferation and differentiation of mESCs through ubiquitination, providing a basis for further exploration of its involvement in embryonic and neural development.

Variants in WASHC3, a component of the WASH complex, cause short stature, variable neurodevelopmental abnormalities, and distinctive facial dysmorphism

Variants in WASHC3, a component of the WASH complex, cause short stature, variable neurodevelopmental abnormalities, and distinctive facial dysmorphism

Microplastics/nanoplastics and neurological health: An overview of neurological defects and mechanisms.

The widespread use of plastic products worldwide has brought about serious environmental issues. In natural environments, it's difficult for plastic products to degrade completely, and so they exist in the form of micro/nanoplastics (M/NPs), which have become a new type of pollutant. Prolonged exposure to M/NPs can lead to a series of health problems in humans, particularly toxicity to the nervous system, with consequences including neurodevelopmental abnormalities, neuronal death, neurological inflammation, and neurodegenerative diseases. Although direct evidence from humans is still limited, model organisms and organoids serve as powerful tools to provide important insights. This article summarizes the effects of M/NPs on the nervous system, focusing on cognitive function, neural development, and neuronal death. Mechanisms such as neurotransmitter synthesis and release, inflammatory responses, oxidative stress, the gut-brain axis, and the liver-brain axis are covered. The neurotoxicity induced by M/NPs may exacerbate or directly trigger neurodegenerative diseases and neurodevelopmental disorders. We particularly emphasize potential therapeutic agents that may counteract the neurotoxic effects induced by M/NPs, highlighting a novel future research direction. In summary, this paper cites evidence and provides mechanistic perspectives on the effects of M/NPs on neurological health, providing clues for eliminating M/NP hazards to human health in the future.

Prenatal Exposure to MAM Impairs mPFC and Hippocampal Inhibitory Function in Mice during Adolescence and Adulthood.

Neurodevelopmental abnormalities are considered to be one of the important causes of schizophrenia. The offspring of methylazoxymethanol acetate (MAM)-exposed mice are recognized for the dysregulation of neurodevelopment and are well-characterized with schizophrenia-like phenotypes. However, the inhibition-related properties of the medial prefrontal cortex (mPFC) and hippocampus throughout adolescence and adulthood have not been systematically elucidated. In this study, both 10 and 15 mg/kg MAM-exposed mice exhibited schizophrenia-related phenotypes in both adolescence and adulthood, including spontaneous locomotion hyperactivity and deficits in prepulse inhibition. We observed that there was an obvious parvalbumin (PV) loss in the mPFC and hippocampus of MAM-exposed mice, extending from adolescence to adulthood. Moreover, the frequency of spontaneous inhibitory postsynaptic currents (sIPSCs) in pyramidal neurons at mPFC and hippocampus was significantly dampened in the 10 and 15 mg/kg MAM-exposed mice. Furthermore, the firing rate of putative pyramidal neurons in mPFC and hippocampus was increased, while that of putative inhibitory neurons was decreased during both adolescence and adulthood. In conclusion, PV loss in mPFC and hippocampus of MAM-exposed mice may contribute to the impaired inhibitory function leading to the attenuation of inhibition in the brain both in vitro and in vivo.

25 years into research with the Méhes Scale, a comprehensive scale of modern dysmorphology.

It has been recognized that subtle, cosmetically insignificant anomalies tend to occur cumulatively in diseases with neurodevelopmental origin. These visible signs of morphogenesis errors are called minor physical anomalies (MPAs), serving as sensitive external markers of abnormal neurodevelopment. After the introduction of the Waldrop Scale, the studies conducted on MPAs in diseases with neurodevelopmental origin gave conflicting results. It has been debated that this discrepancy can be - at least partly - attributed to the use of the Waldrop Scale. Understanding the need of a comprehensive scale of MPAs that also differentiates according to the time of development, Hungarian pediatrician professor of University of Pécs, Károly Méhes developed a scale with 57 items, the only scale differentiating minor malformations from phenogenetic variants. With the use of the Méhes Scale, our research group has been investigating the role of abnormal neurodevelopment in different neuropsychiatric and neurologic disorders since 1997. 25 years into our research, in this review we summarize the results of our 18 research articles on MPAs in different diseases. We have found an increased number of MPAs, especially in the head and mouth region, in patients with schizophrenia, bipolar disorder, Tourette syndrome, autism and many epilepsy syndromes, fortifying the role of abnormal neurodevelopment in these diseases. Moreover, an increased number of MPAs was detected among the first-degree relatives of patients with schizophrenia and bipolar I disorder, supporting the hypothesis about MPAs being endophenotypic trait markers.

Creation of a novel zebrafish model with low DHA status to study the role of maternal nutrition during neurodevelopment

Docosahexaenoic acid (DHA), a dietary omega-3 fatty acid, is a major building block of brain cell membranes. Offspring rely on maternal DHA transfer to meet their neurodevelopmental needs, but DHA sources are lacking in the American diet. Low DHA status is linked to altered immune responses, white matter defects, impaired vision, and an increased risk of psychiatric disorders during development. However, the underlying cellular mechanisms involved are largely unknown, and advancements in the field have been limited by the existing tools and animal models. Zebrafish are an excellent model for studying neurodevelopmental mechanisms. Embryos undergo rapid external development and are optically transparent, enabling direct observation of individual cells and dynamic cell-cell interactions in a way that is not possible in rodents. Here, we create a novel DHA-deficient zebrafish model by 1) disrupting elovl2, a key gene in the DHA biosynthesis pathway, via CRISPR-Cas9 genome editing, and 2) feeding mothers a DHA-deficient diet. We show that low DHA status during development is associated with an abnormal eye phenotype and demonstrate that even morphologically normal siblings exhibit dysregulated vision and stress response gene pathways. Future work using our zebrafish model could reveal the cellular and molecular mechanisms by which low DHA status leads to neurodevelopmental abnormalities, and provide insight into maternal nutritional strategies that optimize infant brain health.

Deficiency of DDX3X results in neurogenesis defects and abnormal behaviors via dysfunction of the Notch signaling

The molecular mechanisms underlying the neurodevelopmental disorders (NDDs) caused by DDX3X variants remain poorly understood. In this study, we validated that de novo DDX3X variants are enriched in female developmental delay (DD) patients and mainly affect the evolutionarily conserved amino acids based on a meta-analysis of 46,612 NDD trios. We generated a ddx3x deficient zebrafish allele, which exhibited reduced survival rate, DD, microcephaly, adaptation defects, anxiolytic behaviors, social interaction deficits, and impaired spatial recognitive memory. As revealed by single-nucleus RNA sequencing and biological validations, ddx3x deficiency leads to reduced neural stem cell pool, decreased total neuron number, and imbalanced differentiation of excitatory and inhibitory neurons, which are responsible for the behavioral defects. Indeed, the supplementation of L-glutamate or glutamate receptor agonist ly404039 could partly rescue the adaptation and social deficits. Mechanistically, we reveal that the ddx3x deficiency attenuates the stability of the crebbp mRNA, which in turn causes downregulation of Notch signaling and defects in neurogenesis. Our study sheds light on the molecular pathology underlying the abnormal neurodevelopment and behavior of NDD patients with DDX3X mutations, as well as providing potential therapeutic targets for the precision treatment.