Disorder Of Neural Development Research Articles

Pathogenic mechanism and therapeutic intervention of impaired N7-methylguanosine (m7G) tRNA modification

Mutations modification enzymes including the tRNA N7-methylguanosine (m7G) methyltransferase complex component WDR4 were frequently found in patients with neural disorders, while the pathogenic mechanism and therapeutic intervention strategies are poorly explored. In this study, we revealed that patient-derived WDR4 mutation leads to temporal and cell-type-specific neural degeneration, and directly causes neural developmental disorders in mice. Mechanistically, WDR4 point mutation disrupts the interaction between WDR4 and METTL1 and accelerates METTL1 protein degradation. We further uncovered that impaired tRNA m7G modification caused by Wdr4 mutation decreases the mRNA translation of genes involved in mTOR pathway, leading to elevated endoplasmic reticulum stress markers, and increases neural cell apoptosis. Importantly, treatment with stress-attenuating drug Tauroursodeoxycholate (TUDCA) significantly decreases neural cell death and improves neural functions of the Wdr4 mutated mice. Moreover, adeno-associated virus mediated transduction of wild-type WDR4 restores METTL1 protein level and tRNA m7G modification in the mouse brain, and achieves long-lasting therapeutic effect in Wdr4 mutated mice. Most importantly, we further demonstrated that both TUDCA treatment and WDR4 restoration significantly improve the survival and functions of human iPSCs-derived neuron stem cells that harbor the patient's WDR4 mutation. Overall, our study uncovers molecular insights underlying WDR4 mutation in the pathogenesis of neural diseases and develops two promising therapeutic strategies for treatment of neural diseases caused by impaired tRNA modifications.

Genetic and Environmental Factors Co-Contributing to Behavioral Abnormalities in adnp/adnp2 Mutant Zebrafish.

Human mutations of ADNP and ADNP2 are known to be associated with neural developmental disorders (NDDs), including autism spectrum disorders (ASDs) and schizophrenia (SZ). However, the underlying mechanisms remain elusive. In this study, using CRISPR/Cas9 gene editing technology, we generated adnp and adnp2 mutant zebrafish models, which exhibited developmental delays, brain deficits, and core behavioral features of NDDs. RNA sequencing analysis of adnpa-/-; adnpb-/- and adnp2a-/-; adnp2b-/- larval brains revealed altered gene expression profiles affecting synaptic transmission, autophagy, apoptosis, microtubule dynamics, hormone signaling, and circadian rhythm regulation. Validation using whole-mount in situ hybridization (WISH) and real-time quantitative PCR (qRT-PCR) corroborated these findings, supporting the RNA-seq results. Additionally, loss of adnp and adnp2 resulted in significant downregulation of pan-neuronal HuC and neuronal fiber network α-Tubulin signals. Importantly, prolonged low-dose exposure to environmental endocrine disruptors (EEDs) aggravated behavioral abnormalities in adnp and adnp2 mutants. This comprehensive approach enhances our understanding of the complex interplay between genetic mutations and environmental factors in NDDs. Our findings provide novel insights and experimental foundations into the roles of adnp and adnp2 in neurodevelopment and behavioral regulation, offering a framework for future preclinical drug screening aimed at elucidating the pathogenesis of NDDs and related conditions.

Reduction of Glyoxalase 1 Expression Links Fetal Methylmercury Exposure to Autism Spectrum Disorder Pathogenesis.

Glyoxalase 1 (Glo1) is an essential enzyme to detoxify methylglyoxal (MGO), a cytotoxic byproduct of glycolysis. Accumulating studies have shown an important role of Glo1 in regulating cortical development and neurogenesis, potentially contributing to the pathogenesis of autism spectrum disorder (ASD) when impaired. We have previously shown that prenatal exposure to non-apoptotic low-dose methylmercury (MeHg), an environmental pollutant, induces premature cortical neurogenesis and ASD-like behaviors in a rodent model. In this study, we aimed to determine the underlying molecular mechanisms that mediate prenatal MeHg-induced premature neuronal differentiation and abnormal neurodevelopment. Using single-cell RNA sequencing (scRNA-seq) and real-time quantitative PCR (RT-qPCR), we found that prenatal MeHg exposure at a non-apoptotic dose significantly reduced Glo1 gene expression in embryonic cultured radial glia precursors (RGPs). In cultured RGPs, the knockdown of Glo1 expression increased neuronal production at the expense of the cultured RGPs population, while overexpression of Glo1 restored MeHg-induced neuronal differentiation back to normal levels. Furthermore, we found that co-treatment with both MeHg and multiple MGO scavengers or a CREB inhibitor (iCREB) mitigated MeHg-induced premature neuronal differentiation, reinforcing the role of Glo1 and CREB in mediating MeHg-induced neuronal differentiation. Our findings demonstrate a direct link between MeHg exposure and expression of an ASD risk gene Glo1 in cortical development, supporting the important role of gene-environment interaction in contributing to the etiology of neural developmental disorders, such as ASD.

Moderate Physical Activity Increases the Expression of ADNP in Rat Brain.

Activity-dependent neuroprotective protein (ADNP) is a neuroprotective protein essential for embryonic development, proper brain development, and neuronal plasticity. Its mutation causes the autism-like ADNP syndrome (also called the Helsmoortel-Van der Aa syndrome), characterized by neural developmental disorders and motor dysfunctions. Similar to the ADNP syndrome, the ADNP haploinsufficient mouse shows low synapse density, leading to motor and cognitive ability delays. Moderate physical activity (PA) has several neuroprotective and cognitive benefits, promoting neuronal survival, differentiation, neurogenesis, and plasticity. Until now, no study has investigated the effect of moderate exercise on ADNP expression and distribution in the rat brain. The aim of the current investigation was to study the effects of moderate exercise on the ADNP expression and neuronal activation measured by the microtubule protein β-Tubulin III. In pursuit of this objective, twenty-four rats were selected and evenly distributed into two categories: sedentary control rats and rats exposed to moderate physical activity on a treadmill over a span of 12 weeks. Our results showed that moderate PA increases the expression of ADNP and β-Tubulin III in the dentate gyrus (DG) hippocampal region and cerebellum. Moreover, we found a co-localization of ADNP and β-Tubulin III in both DG and cerebellum, suggesting a direct association of ADNP with adult neuronal activation induced by moderate PA.

RNF220-mediated K63-linked polyubiquitination stabilizes Olig proteins during oligodendroglial development and myelination.

Maldevelopment of oligodendroglia underlies neural developmental disorders such as leukodystrophy. Precise regulation of the activity of specific transcription factors (TFs) by various posttranslational modifications (PTMs) is required to ensure proper oligodendroglial development and myelination. However, the role of ubiquitination of these TFs during oligodendroglial development is yet unexplored. Here, we find that RNF220, a known leukodystrophy-related E3 ubiquitin ligase, is required for oligodendroglial development. RNF220 depletion in oligodendrocyte lineage cells impedes oligodendrocyte progenitor cell proliferation, differentiation, and (re)myelination, which consequently leads to learning and memory defects. Mechanistically, RNF220 targets Olig1/2 for K63-linked polyubiquitination and stabilization during oligodendroglial development. Furthermore, in a knock-in mouse model of leukodystrophy-related RNF220R365Q mutation, the ubiquitination and stabilization of Olig proteins are deregulated in oligodendroglial cells. This results in pathomimetic oligodendroglial developmental defects, impaired myelination, and abnormal behaviors. Together, our evidence provides an alternative insight into PTMs of oligodendroglial TFs and how this essential process may be implicated in the etiology of leukodystrophy.

WORKING MEMORY IN AUTISM: A REVIEW. EXECUTIVE FUNCTION OR COMPLEXITY THEORY?

Autism is a disorder of neural development characterised by social impairments, communication difficulties, and by restricted and repetitive activities, and executive function (EF) problems are often seen throughout the spectrum. Working Memory (WM) is a temporary storage system under attentional control that actively holds multiple pieces of transitory information in the mind. WM is a part of the executive functions, which is an umbrella term for cognitive processes that regulate, control, and manage other cognitive processes, for instance planning and attention. This article shows that studies supporting either executive function or complexity theory do not correlate and that attention should be oriented not to performance levels in WM tasks but to the strategies and resources employed in verbal and visuospatial memory during the life cycle.

SynCAMs in Normal Vertebrate Neural Development and Neuropsychiatric Disorders: from the Perspective of the OCAs.

Neuronal synaptic junctions connect neurons to enable neuronal signal transmission in the nervous system. The proper establishment of synaptic connections required many adhesion molecules. Malfunctions of these adhesion molecules can result in neural development disorders and neuropsychiatric disorders. How specific synapses are established by various adhesion molecules for proper neural circuitry is a fundamental question of neuroscience. SynCAMs, also named CADMs, Necl, etc., are among the many adhesion proteins found in synapses. Here, we review the current understanding of the physical properties of SynCAMs and their roles in axon pathfinding, myelination, synaptogenesis, and synaptic plasticity. In addition, we discuss the involvement of SynCAMs in neuropsychiatric disorders. Finally, we propose that SynCAM functions can be better viewed and understood from the perspective of orientational cell adhesions (OCAs). In particular, we discuss the possibilities of how SynCAMs can be regulated at the cell-type specific expression, transcription variants, posttranslational modification, and subcellular localization to modulate the diversity of SynCAMs as OCA molecules. Being major components of the synapses, SynCAMs continue to be an important research topic of neuroscience, and many outstanding questions are waiting to be answered.

Inhibitory control associated with the neural mechanism of joint attention in preschoolers: An fNIRS evidence

Joint attention (JA) is fundamental to the development of children's social functioning; both its response and initiation are closely related to executive function (EF), but the relationship between JA and EF has been relatively rarely studied. The present study aimed to investigate the between-condition differences in brain activation and synchronization of JA under four conditions: (1) stranger-Initiating Joint Attention (Stranger-IJA); (2) teacher-Initiating Joint Attention (Teacher-IJA); (3) stranger-Responding to Joint Attention (Stranger-RJA); and (4) teacher-Responding to Joint Attention (Teacher-RJA). It also aimed to explore the relationships between neuroimaging data and children's inhibitory control levels. To address these two goals, the present study employed 41 (aged 58.61 ± 8.64 months, 24 boys) preschool children through behavioral and functional Near-Infrared Spectroscopy (fNIRS) brain imaging assessment to measure children's EF and brain function under JA, respectively. The results revealed that: (1) a significantly higher prefrontal cortex (PFC) activation was triggered in IJA than RJA; (2) a significantly higher brain activation was triggered in JA with a stranger than with a teacher; (3) a significantly higher index of synchronization asymmetry was evoked in the left and right PFC during interaction with the teacher than with the stranger; and (4) preschoolers' brain activation and synchronization were correlated with their inhibitory control level. The findings advance our understanding of preschoolers' social cognitive development with a biological aspect, offer an opportunity to understand the potential risk of the neural disorder in preschoolers, and provide a basis and insight for preventing neural developmental disorders.

Triazole fungicides exert neural differentiation alteration through H3K27me3 modifications: In vitro and in silico study

Considering that humans are unavoidably exposed to triazole fungicides through the esophagus, respiratory tract, and skin contact, revealing the developmental toxicity of triazole fungicides is vital for health risk assessment. This study aimed to screen and discriminate neural developmental disorder chemicals in commonly used triazole fungicides, and explore the underlying harmful impacts on neurogenesis associated with histone modification abnormality in mouse embryonic stem cells (mESCs). The triploblastic and neural differentiation models were constructed based on mESCs to expose six typical triazole fungicides (myclobutanil, tebuconazole, hexaconazole, propiconazole, difenoconazole, and flusilazole). The result demonstrated that although no cytotoxicity was observed, different triazole fungicides exhibited varying degrees of alterations in neural differentiation, including increased ectodermal differentiation, promoted neurogenesis, increased intracellular calcium ion levels, and disturbance of neurotransmitters. Molecular docking, cluster analysis, and multiple linear regressions demonstrated that the binding affinities between triazole fungicides and the Kdm6b-ligand binding domain were the dominant determinants of the neurodevelopmental response. This partially resulted in the reduced enrichment of H3K27me3 at the promoter region of the serotonin receptor 2 C gene, finally leading to disturbed neural differentiation. The data suggested potential adverse outcomes of triazole fungicides on embryonic neurogenesis even under sublethal doses through interfering histone modification, providing substantial evidence on the safety control of fungicides.

Role of brahma-related gene 1/brahma-associated factor subunits in neural stem/progenitor cells and related neural developmental disorders.

Different fates of neural stem/progenitor cells (NSPCs) and their progeny are determined by the gene regulatory network, where a chromatin-remodeling complex affects synergy with other regulators. Here, we review recent research progress indicating that the BRG1/BRM-associated factor (BAF) complex plays an important role in NSPCs during neural development and neural developmental disorders. Several studies based on animal models have shown that mutations in the BAF complex may cause abnormal neural differentiation, which can also lead to various diseases in humans. We discussed BAF complex subunits and their main characteristics in NSPCs. With advances in studies of human pluripotent stem cells and the feasibility of driving their differentiation into NSPCs, we can now investigate the role of the BAF complex in regulating the balance between self-renewal and differentiation of NSPCs. Considering recent progress in these research areas, we suggest that three approaches should be used in investigations in the near future. Sequencing of whole human exome and genome-wide association studies suggest that mutations in the subunits of the BAF complex are related to neurodevelopmental disorders. More insight into the mechanism of BAF complex regulation in NSPCs during neural cell fate decisions and neurodevelopment may help in exploiting new methods for clinical applications.

Correlation of Electrophysiological and Gene Transcriptional Dysfunctions in Single Cortical Parvalbumin Neurons After Noise Trauma

Parvalbumin-expressing (PV+) interneurons in the sensory cortex form powerful inhibitory synapses on the perisomatic compartments and axon initial segments of excitatory principal neurons (PNs), and perform diverse computational functions. Impaired PV+ interneuron functions have been reported in neural developmental and degenerative disorders. Expression of the unique marker parvalbumin (PV) is often used as a proxy of PV+ interneuron functions. However, it is not entirely clear how PV expression is correlated with PV+ interneuron properties such as spike firing and synaptic transmission. To address this question, we characterized electrophysiological properties of PV+ interneurons in the primary auditory cortex (AI) using whole-cell patch clamp recording, and analyzed the expression of several genes in samples collected from single neurons using the patch pipettes. We found that, after noise induced hearing loss (NIHL), the spike frequency adaptation increased, and the expression of PV, glutamate decarboxylase 67 (GAD67) and Shaw-like potassium channel (KV3.1) decreased in PV+ neurons. In samples prepared from the auditory cortical tissue, the mRNA levels of the target genes were all pairwise correlated. At the single neuron level, however, the expression of PV was significantly correlated with the expression of GAD67, but not KV3.1, maximal spike frequency, or spike frequency adaptation. The expression of KV3.1 was correlated with spike frequency adaptation, but not with the expression of GAD67. These results suggest separate transcriptional regulations of PV/GAD67 vs. KV3.1, both of which are modulated by NIHL.

Neurogenesis Potential Evaluation and Transcriptome Analysis of Fetal Hypothalamic Neural Stem/Progenitor Cells With Prenatal High Estradiol Exposure.

High maternal estradiol is reported to induce metabolic disorders by modulating hypothalamic gene expression in offspring. Since neurogenesis plays a crucial role during hypothalamus development, we explored whether prenatal high estradiol exposure (HE) affects proliferation and differentiation of fetal hypothalamic neural stem/progenitor cells (NSC/NPCs) in mice and performed RNA sequencing to identify the critical genes involved. NSC/NPCs in HE mice presented attenuated cell proliferation but increased neuronal differentiation in vitro compared with control (NC) cells. Gene set enrichment analysis of mRNA profiles indicated that genes downregulated in HE NSC/NPCs were enriched in neurogenesis-related Gene Ontology (GO) terms, while genes upregulated in HE NSC/NPCs were enriched in response to estradiol. Protein-protein interaction analysis of genes with core enrichment in GO terms of neurogenesis and response to estradiol identified 10 Hub mRNAs, among which three were potentially correlated with six differentially expressed (DE) lncRNAs based on lncRNA profiling and co-expression analysis. These findings offer important insights into developmental modifications in hypothalamic NSC/NPCs and may provide new clues for further investigation on maternal environment programmed neural development disorders.

RIPK3-Dependent Necroptosis Is Induced and Restricts Viral Replication in Human Astrocytes Infected With Zika Virus.

Apoptosis, pyroptosis and necroptosis are regulated processes of cell death which can be crucial for viral disease outcomes in hosts because of their effects on viral pathogenicity and host resistance. Zika virus (ZIKV) is a mosquito-borne flavivirus, which infects humans and can cause neurological disorders. Neural developmental disorders and microcephaly could occur in infected fetuses. Several types of nervous cells have been reported to be susceptible to ZIKV infection. Human astrocytes play important roles in the nutritional support and defense of neurons. In this study, we show that human astrocytes are susceptible to ZIKV infection and undergo progressive cell death after infection. In infected astrocytes we detected no cleavage or activation of pro-caspase-3 and pro-caspase-1. Apoptotic substrates and increased secretion of interleukin (IL)-1β or IL-18 were not detected, either. These ruled out the occurrence of apoptosis or pyroptosis in ZIKV-infected astrocytes. We detected, however, an increase of phosphorylated receptor-interacting serine/threonine-protein kinase (RIPK)1, RIPK3, and mixed lineage kinase domain-like (MLKL) protein, indicating that programmed necrosis, or necroptosis, was induced in infected astrocytes. The phosphorylation and cell death were inhibited in cells pre-treated with GSK’872, an inhibitor of RIPK3, while inhibition of RIPK1 with an inhibitor, Necrostatin-1, had no effect, suggesting that ZIKV-induced necroptosis was RIPK1-independent in astrocytes. Consistent with this finding, the inhibition of RIPK1 had no effect on the phosphorylation of MLKL. We showed evidence that MLKL phosphorylation was RIPK3-dependent and ZBP-1, which could stimulate RIPK3, was upregulated in ZIKV-infected astrocytes. Finally, we demonstrated that in GSK’872-pre-treated astrocytes, viral replication increased significantly, which indicates that necroptosis may be protective against viral replication in astrocytes. Our finding that astrocytes uniquely underwent necroptosis in response to ZIKV infection provides insight and helps us better understand the viral pathogenesis in the ZIKV-infected central nervous system.

Mitochondria Control Cortical Cell Fate after Mitosis.

During brain development, the daughter cells of neural stem cells have to make a choice - either to become new stem cells or to differentiate into neurons. In a recent issue of Science, Iwata etal. (2020) show that these fate decisions can be determined after mitosis by mitochondrial remodeling.

ADNP Controls Gene Expression Through Local Chromatin Architecture by Association With BRG1 and CHD4.

ADNP (Activity Dependent Neuroprotective Protein) is proposed as a neuroprotective protein whose aberrant expression has been frequently linked to rare neural developmental disorders and cancers, including the recently described neurodevelopmental Helsmoortel-Van der Aa syndrome. Recent studies have suggested that ADNP functions as an important chromatin regulator. However, how ADNP-regulated chromatin mechanisms control gene expression and stem cell fate commitment remains unclear. Here we show that ADNP interacts with two chromatin remodelers, BRG1 and CHD4. ADNP is required for proper establishment of chromatin accessibility, nucleosome configuration, and bivalent histone modifications of developmental genes. Loss of ADNP leads to enhancer over-activation and increased ratio of H3K4me3/H3K27me3 at key primitive endoderm (PrE) gene promoters, resulting in prominent up-regulation of these genes and priming ES cell differentiation toward endodermal cell types. Thus, our work revealed a key role of ADNP in the establishment of local chromatin landscape and structure of developmental genes by association with BRG1 and CHD4. These findings provide further insights into the role of ADNP in the pathology of the Helsmoortel-Van der Aa syndrome.

ADNP promotes neural differentiation by modulating Wnt/\u03b2-catenin signaling

ADNP (Activity Dependent Neuroprotective Protein) is a neuroprotective protein whose aberrant expression has been frequently linked to neural developmental disorders, including the Helsmoortel-Van der Aa syndrome (also called the ADNP syndrome). However, its role in neural development and pathology remains unclear. Here, we show that ADNP is required for neural induction and differentiation by enhancing Wnt signaling. Mechanistically, ADNP functions to stabilize β-Catenin through binding to its armadillo domain which prevents its association with key components of the degradation complex: Axin and APC. Loss of ADNP promotes the formation of the degradation complex and β-Catenin degradation via ubiquitin-proteasome pathway, resulting in down-regulation of key neuroectoderm developmental genes. In addition, adnp gene disruption in zebrafish leads to defective neurogenesis and reduced Wnt signaling. Our work provides important insights into the role of ADNP in neural development and the pathology of the Helsmoortel-Van der Aa syndrome caused by ADNP gene mutation.

The comorbidity of fetal alcohol syndrome and sleep apnea/hypopnea syndrome in a 7‑year-old girl (a clinical case)

Fetal alcohol syndrome is the result of prenatal effect of alcohol on the fetus and manifests as disorders of neural and mental development and various congenital developmental disorders leading to comorbid diseases. Among congenital developmental disorders for the pathology, adenotonsillar pathology was described. Narrowing of the nasopharyngeal opening, faciomaxillary dysmorphias and muscle hypotony can lead to sleep apnea syndrome. The article presents a clinical case of fetal alcohol syndrome and sleep apnea in a 7‑year-old girl with multiple developmental disorders born form alcohol-abusing mother. Breathing abnormalities during sleep must be differentiated per character and cause. Cardiorespiratory monitoring is used to diagnose respiratory abnormalities, the results determine patient management tactics. Interdisciplinary approach to observation and treatment of a child with fetal alcohol syndrome is necessary to increase the effectiveness of rehabilitation measures and patient’s quality of life.

A study of magnitude of zinc deficiency and effectiveness of zinc supplementation among elderly with zinc deficiency

INTRODUCTION: Despite the significant role played by Zinc, the body stores of Zinc are very minimal and easily depleted. Zinc deficiency is known to be associated with various pathological conditions, including impaired immunity, delayed wound healing, retarded growth, neural development disorders and degenerative diseases. The loss experienced due to zinc deficiency sums to nearly 16 million global disability-adjusted life years (DALYs). This study focuses on the magnitude of Zinc deficiency and the effect of Zinc Supplementation among the hospitalized Elderly. MATERIALS AND METHODS: A prospective interventional study has been carried out in Department of General Medicine, JSS medical college and hospital, Mysore, from November 2016 to August 2018. The serum zinc level was assessed by Zinc Colorimetric Method. Tools like Geriatric Depression Scale (GDS), Mini Nutritional Assessment (MNA)-SF and The KATZ Index of Independence in Activities of Daily Living were used to collect relevant data from the participants. RESULTS: A total of 100 elderly subjects were included in the final analysis. 38(38%) people had normal Zinc level. The mean serum Zinc levels pre and post interventions were reported to be 7.27 ± 1.33 gm/dl and 11.49 ± 1.83 gm/dl respectively. The difference in the pre and post intervention serum Zinc level was statistically significant (P value CONCLUSION: The magnitude of zinc deficiency is noted in majority of the subjects. Supplementation in old age has a positive effect in Zinc levels. As ageing is a risk factor for Zinc deficiency, prophylactic doses of Zinc could be an option to prevent Zinc deficiency.

Prenatal incubation temperature affects neonatal precocial birds' locomotor behavior

Temperature during the prenatal period is an important factor for developing embryos. Extensive human and animal research indicate embryos are sensitive to small fluctuations in temperature which has profound effects on phenotype development. Much of this research has focused on survivability, morphology, and incubation duration, but comparatively less in known about how prenatal temperature influences the development of motor coordination. In this study, we experimentally tested whether exposure to naturally occurring cool (36.9 °C) or warm (38.1 °C) thermal conditions for a brief period (4 days) during early incubation can influence postnatal motor performance in neonatal bobwhite quail hatchlings. We compared gait spatiotemporal parameters, body kinematics, and locomotive behaviors of control chicks incubated in an optimal thermal environment (37.5 °C) with thermally manipulated chicks. Experimental temperature treatment began on embryonic day five (E5) and ended on E8. Chicks were tested 24-h after hatching. Cool thermal exposure during incubation delayed hatching, reduced body mass, and increased fall frequency, intertarsal joint angle and stride length variability during the gait task compared to optimally incubated chicks. Warm thermal exposure during incubation delayed bone growth and increased fall frequency relative to controls. We discuss the relationship between motor development and thermal regulatory processes and provide insight into how spatiotemporal parameters aid in elucidating subtle differences in coordinated movement which may contribute to atypical motor development and be associated with neural developmental disorders. We provide the first spatiotemporal evidence for the importance of optimal thermal microclimates for typical prenatal motor development.

Mga Modulates Bmpr1a Activity by Antagonizing Bs69 in Zebrafish.

MAX giant associated protein (MGA) is a dual transcriptional factor containing both T-box and bHLHzip DNA binding domains. In vitro studies have shown that MGA functions as a transcriptional repressor or activator to regulate transcription of promotors containing either E-box or T-box binding sites. BS69 (ZMYND11), a multidomain-containing (i.e., PHD, BROMO, PWWP, and MYND) protein, has been shown to selectively recognizes histone variant H3.3 lysine 36 trimethylation (H3.3K36me3), modulates RNA Polymerase II elongation, and functions as RNA splicing regulator. Mutations in MGA or BS69 have been linked to multiple cancers or neural developmental disorders. Here, by TALEN and CRISPR/Cas9-mediated loss of gene function assays, we show that zebrafish Mga and Bs69 are required to maintain proper Bmp signaling during early embryogenesis. We found that Mga protein localized in the cytoplasm modulates Bmpr1a activity by physical association with Zmynd11/Bs69. The Mynd domain of Bs69 specifically binds the kinase domain of Bmpr1a and interferes with its phosphorylation and activation of Smad1/5/8. Mga acts to antagonize Bs69 and facilitate the Bmp signaling pathway by disrupting the Bs69–Bmpr1a association. Functionally, Bmp signaling under control of Mga and Bs69 is required for properly specifying the ventral tailfin cell fate.