Biology subjects

Tang, Z.

Publications and source records attributed to Tang, Z..

At least 109 records · Page 6Linked to original sources

bioRxiv2022

SiGra: Single-cell spatial elucidation through image-augmented graph transformer

The recent advances in high-throughput molecular imaging push the spatial transcriptomics technologies to the subcellular resolution, which breaks the limitations of both single-cell RNA-seq and array-based spatial profiling. The latest released single-cell spatial transcriptomics data from NanoString CosMx and MERSCOPE platforms contains multi-channel immunohistochemistry images with rich information of cell types, functions, and morphologies of cellular compartments. In this work, we developed a novel method, Single-cell spatial elucidation through image-augmented Graph transformer (SiGra), to reveal spatial domains and enhance the substantially sparse and noisy transcriptomics data. SiGra applies hybrid graph transformers over a spatial graph that comprises high-content images and gene expressions of individual cells. SiGra outperformed state-of-the-art methods on both single-cell spatial profiles and spot-level spatial transcriptomics data from complex tissues. The inclusion of immunohistochemistry images improved the model performance by 37% (95%CI: 27% - 50%). SiGra improves the characterization of intratumor heterogeneity and intercellular communications in human lung cancer samples, meanwhile recovers the known microscopic anatomy in both human brain and mouse liver tissues. Overall, SiGra effectively integrates different spatial modality data to gain deep insights into the spatial cellular ecosystems.

bioinformatics↗

bioRxiv2022

Mechanistic basis for targeting homologous recombination defective liver cancer via synthetic lethality

Many cancers harbour homologous recombination defects (HRD). The identification of PARP inhibitors as synthetic lethal with HRD has led to new therapeutic strategies for HRD cancers. Here we report a subtype of HRD that is caused by the perturbation of a previously uncharacterised proteasome variant, CDW19S, in hepatitis virus B (HBV) positive hepatocellular carcinoma (HBVHCC). CDW19S contains the 19S complex decorated with a Cullin 4 ubiquitin ligase (CRL4WDR70) that is assembled at broken chromatin and regulates end processing nucleases. The HBV oncoprotein, HBx, prevents integration of the CRL4 backbone into CDW19S. We show that CDW19S directly ubiquitinates ADRM1Rpn13, targeting it for degradation, and that HBx interferes with this, leading to the imposition of a novel ADRM1Rpn13-dependent resection barrier that results in HRD and promotes carcinogenesis with concurrent TP53 loss. Using cellular and patient-derived xenograft models we demonstrate that HRD in HBVHCC can be exploited to restrict tumour progression. Our work clarifies the mechanism of a virally-induced HRD and suggests a new route for targeted HBVHCC therapy.

cancer biology↗

bioRxiv2022

Spatial Atlas of the Mouse Central Nervous System at Molecular Resolution

Spatially charting molecular cell types at single-cell resolution across the three-dimensional (3D) volume of the brain is critical for illustrating the molecular basis of the brain anatomy and functions. Single-cell RNA sequencing (scRNA-seq) has profiled molecular cell types in the mouse brain1, 2, but cannot capture their spatial organization. Here, we employed an in situ sequencing technique, STARmap PLUS3, 4, to map more than one million high-quality cells across the whole adult mouse brain and the spinal cord, profiling 1,022 genes at subcellular resolution with a voxel size of 194 X 194 X 345 nm in 3D. We developed computational pipelines to segment, cluster, and annotate 231 molecularly defined cell types and 64 tissue regions with single-cell resolution. To create a transcriptome-wide spatial atlas, we further integrated the STARmap PLUS measurements with a published scRNA-seq atlas1, imputing 11,844 genes at the single-cell level. Finally, we engineered a highly expressed RNA barcoding system to delineate the tropism of a brain-wide transgene delivery tool, AAV-PHP.eB5, 6, revealing its single-cell resolved transduction efficiency across the molecular cell types and tissue regions of the whole mouse brain. Together, our datasets and annotations provide a comprehensive, high-resolution single-cell resource that integrates a spatial molecular atlas, cell taxonomy, brain anatomy, and genetic manipulation accessibility of the mammalian central nervous system (CNS).

neuroscience↗

bioRxiv2022

The radio-protective effects of (-)-Epigallocatechin-3-gallate (EGCG): regulating macrophage function in radiation-induced intestinal injury.

Accidental and medical radiation exposure may cause radiation-induced intestinal injury (RIII), a catastrophic disease requiring efficient therapies. (-)-Epigallocatechin-3-gallate (EGCG), a major constituent of green tea, has been shown to have potent biological activity as well as strong anti-inflammation effects. Here, we demonstrate that EGCG treatment not only protects mice against total body irradiation (TBI)-induced toxicity and weight loss but also alleviates whole abdominal irradiation (WAI)-induced intestinal injury. EGCG promotes proliferation and survival of intestinal stem cells, inhibits radiation-induced apoptosis and inflammation. At the same time, EGCG preserves the composition of the gut microbiota in WAI mice. In vitro, we demonstrate that EGCG regulates the release of radiation-induced inflammatory factors by inhibiting inflammatory pathways such as toll-like receptor signaling pathway in peritoneal macrophages. Mechanistically, the radioprotective effect of EGCG was likely attributable to its preservation on macrophages and the colonized gut microbiota composition, thus relieving the intestinal inflammation. EGCG provides a novel strategy to mitigate RIII and improve the prognosis of patients after radiotherapy.

cell biology↗

bioRxiv2022

Evaluating deep learning for predicting epigenomic profiles

Deep learning has been successful at predicting epigenomic profiles from DNA sequences. Most approaches frame this task as a binary classification relying on peak callers to define functional activity. Recently, quantitative models have emerged to directly predict the experimental coverage values as a regression. As new models continue to emerge with different architectures and training configurations, a major bottleneck is forming due to the lack of ability to fairly assess the novelty of proposed models and their utility for downstream biological discovery. Here we introduce a unified evaluation framework and use it to compare various binary and quantitative models trained to predict chromatin accessibility data. We highlight various modeling choices that affect generalization performance, including a downstream application of predicting variant effects. In addition, we introduce a robustness metric that can be used to enhance model selection and improve variant effect predictions. Our empirical study largely supports that quantitative modeling of epigenomic profiles leads to better generalizability and interpretability.

bioinformatics↗

bioRxiv2022

Heat Shock Factor 1 (HSF1) specifically potentiates c-MYC-mediated transcription independently of the canonical heat-shock response

Despite its pivotal roles in biology, how the transcriptional activity of c-MYC is attuned quantitatively remain poorly defined. Here, we show that heat shock factor 1 (HSF1), the master transcriptional regulator of the heat-shock, or proteotoxic stress, response, acts as a key modifier of the c-MYC-mediated transcription. HSF1 deficiency diminishes c-MYC DNA binding and dampens its transcriptional activity genome-widely. Mechanistically, c-MYC, MAX, and HSF1 assemble into a transcription factor complex on genomic DNAs and, surprisingly, the DNA binding of HSF1 is dispensable. Instead, HSF1 physically recruits the histone acetyltransferase GCN5, thereby promoting histone acetylation and augmenting c-MYC transcriptional activity. Thus, our studies reveal that HSF1 specifically potentiates the c-MYC-mediated transcription, distinct from its role in the canonical heat-shock response. Importantly, this mechanism of action engenders two distinct c-MYC activation states, primary and advanced, which may be important to accommodate diverse physiological and pathological conditions.

cancer biology↗

bioRxiv2022

Knockout of OsSWEET15 impaired rice embryo formation and seed-setting

we show that the knockout of a sugar transporter gene OsSWEET15 led to a significant drop in rice fertility because near half of the knockout mutant spikelets bore blighted or empty grains. The rest spikelets bore fertile grains with slightly reduced weight. Notably, the ovaries in the blighted grains of the ossweet15 mutants expanded after flowering but terminated development before the endosperm cellularization stage and aborted subsequently. GUS and GFP representing OsSWEET15 expression showed that the protein was strongly expressed in the embryo surrounding region (ESR) which was supposed to supply nutrients for the embryo development. These results joined with the proteins sucrose transport capacity and plasma membrane localization suggest that OsSWEET15 plays a prominent role during the caryopsis formation stage probably by releasing sucrose from the ESR to support the embryo development. By contrast, the empty grains were probably caused by the reduced pollen viability of the ossweet15 mutants. Investigation of the makeup of ossweet11 mutant grains revealed similar phenotypes that were observed in the ossweet15 mutants. These results indicate that both OsSWETT15 and OsSWEET11 play important and similar roles during rice pollen development, caryopsis formation, and seed-setting in addition to their function in seed-filling that was demonstrated previously.

plant biology↗

bioRxiv2021

A genetic bottleneck of mitochondrial DNA during human lymphocyte development

Mitochondria are essential organelles in eukaryotic cells that provide critical support for energetic and metabolic homeostasis. Mutations that accumulate in mitochondrial DNA (mtDNA) in somatic cells have been implicated in cancer, degenerative diseases, and the aging process. However, the mechanisms used by somatic cells to maintain proper functions despite their mtDNA mutation load are poorly understood. Here, we analyzed somatic mtDNA mutations in more than 30,000 human single peripheral and bone marrow mononuclear cells and observed a significant overrepresentation of homoplastic mtDNA mutations in B, T and NK lymphocytes despite their lower mutational burden than other hematopoietic cells. The characteristic mutational landscape of mtDNA in lymphocytes were validated with data from multiple platforms and individuals. Single-cell RNA-seq and computational modeling demonstrated a stringent mitochondrial bottleneck during lymphocyte development likely caused by lagging mtDNA replication relative to cell proliferation. These results illuminate a potential mechanism used by highly metabolically active immune cells for quality control of their mitochondrial genomes.

genetics↗

bioRxiv2021

Rod-genesis driven by mafba in an nrl knockout zebrafish model with altered photoreceptor compositions and progressive retinal degeneration

The neural retina leucine zipper (NRL) is an essential gene for the fate determination and differentiation of rod photoreceptors in mammals. Mutations in NRL have been associated with autosomal recessive enhanced S-cone syndrome and autosomal dominant retinitis pigmentosa. However, the exact role of Nrl in regulating the development and maintenance of photoreceptors in zebrafish, a popular animal model used for retinal degeneration and regeneration studies, has not been fully determined. In this study, we generated an nrl knockout zebrafish model by CRISPR-Cas9 technology and observed a surprising phenotype characterized by the reduction but not total elimination of rods and the over-grown of green-cones. By tracing the developmental process of rods, we discovered two waves of rod genesis in zebrafish, emerging at the embryonic stage with an nrl-dependent pattern and the post-embryonic stage with an nrl-independent pattern, respectively. Through bulk and single-cell RNA sequencing, we constructed the gene expression profiles for the whole retinal tissues and each of the retinal cell types in WT and nrl knockout zebrafish. We detected the rod/green-cone intermediate photoreceptors in nrl knockout zebrafish, suggesting that there may be a kind of rod/green-cone bipotent precursors and its fate choice between rod and green-cone is controlled by nrl. Besides, we identified the mafba gene as a novel regulator for nrl-independent rods, based on the cell-type-specific expression pattern and the retinal phenotype of nrl/mafba double knockout zebrafish. Furthermore, the altered photoreceptor compositions and abnormal gene expression caused progressive retinal degeneration and subsequent regeneration in nrl knockout zebrafish. Our work revealed a novel function of mafba gene in rod development and established a more suitable model for the developmental processes and regulatory mechanisms of rod and green-cone photoreceptors in zebrafish. Author SummaryVision is mediated by two types of light-sensing cells named rod and cone photoreceptors in animal eyes. Abnormal generation, dysfunction or death of photoreceptor cells can all cause irreversible vision problems. NRL is the most important gene for the occurrence and function of rod cells in mice and humans. Surprisingly, we found that in zebrafish, a popular animal model used for mimicking human diseases and testing treatments, there are two types of rod cells and breaking the function of nrl gene only affects the generation of rod cells at the embryonic stage but not the juvenile and adult stages. The rod cells produced later are proved to be driven by the mafba gene, which has not been reported to play a role in rod cells. In addition to the reduction of rod cells, deletion of nrl also results in the occurrence of rod/green-cone hybrid cells and the increasing number of green-cones. The combination of changes at cellular and molecular levels finally lead to a disease condition named retinal degeneration. These findings add new knowledge to the research field and highlight the conserved and species-specific regulatory mechanisms of photoreceptor development and maintenance.

genetics↗

bioRxiv2021

Rapamycin attenuated zinc-induced tau phosphorylation and oxidative stress in animal model: Involvement of dual mTOR/p70S6K and Nrf2/HO-1 pathways

Alzheimers disease is pathologically featured by abnormal accumulation of amyloid-beta plaque, neurofibrillary tangles, oxidative stress, neuroinflammation, and neurodegeneration. Metal dysregulation including excessive zinc released by presynaptic neurons plays an important role in tau pathology and oxidase activation. The activities of mammalian target of rapamycin (mTOR)/ ribosomal S6 protein kinase (p70S6K) are elevated in the brains of patients with Alzheimers disease. Zinc induces tau hyperphosphorylation via mTOR/P70S6K activation in vitro. However, the involvement of mTOR/P70S6K pathway in zinc-induced oxidative stress, tau degeneration, synaptic and cognitive impairment, has not been fully elucidated in vivo. Here we assessed in the effect of pathological concentration of zinc in SH-SY5Y cells by using biochemical assays and immunofluorescence staining. Rats (n = 18, male) were lateral ventricularly-injected with zinc and treated with rapamycin (intraperitoneal injection) for one week and assessed using Morris water maze. Evaluation of the oxidative stress, tau phorsphylation and synaptic impairment were performed using the hippocampus tissue of the rats by biochemical assays and immunofluorescence staining. Results from Morris water maze showed that the capacity of spatial memory is impaired in zinc-treated rats. Zinc sulfate significantly increased the levels of P-mTOR Ser2448, P-p70S6K Thr389, and P-tau Ser356, and decreased levels of Nrf2 and HO{square}1 in SH-SY5Y cells and in zinc-treated rats compared with control groups. Increased expressions of reactive oxygen species were observed in zinc sulfate-induced SH-SY5Y cells as well as in the hippocampus of zinc-injected rats. Rapamycin, an inhibitor of mTOR, rescued the zinc-induced increases in mTOR/p70S6K activations, tau phosphorylation and oxidative stress, as well as Nrf2/HO{square}1 inactivation, cognitive impairment and synaptic impairment reduced the expression of synapse-related proteins in zinc-injected rats. In conclusion, our findings imply that rapamycin prevents zinc-induced cognitive impairment and protects neurons from tau pathology, oxidative stress and synaptic impairment, by decreasing mTOR/p70S6K hyperactivity and increasing Nrf2/HO {square} 1 activity.

neuroscience↗

bioRxiv2021

BMSC-Derived Exosomal MiRNAs Can Modulate Bone Restoration in Diabetic Rats with Femoral Defects

The exosomal miRNAs of BMSCs participate in hyperglycemia induced poor healing of bone defects. Here, we demonstrate that exosomes derived from BMSCs harvested from diabetes mellitus(DM) rats suppressed bone formation when administered to normal rats with bone defects. Using high-throughput sequencing analysis of microRNA molecules, high miR-140-3p levels were expressed in exosomes released by N-BMSCs. Using TargetScan software and luciferase activity assays, plxnb1 was identified as the downstream molecular target of exosomal miR-140-3p that regulated osteogenesis. Transplantation of exosomes that overexpressed miR-140-3p into DM rats promoted the restoration of bone defects. Furthermore, miR-140-3p significantly promoted the differentiation of DM-BMSCs into osteoblasts and inhibited the expression p-RohA and p-ROCK in the plexin B1 signaling pathway. Taken together, these observations suggest that DM decreases the levels of exosomal miR-140-3p, which impedes bone formation and the differentiation of BMSCs. MiR-140-3p may represent a potential therapeutic target for DM related to abnormal bone metabolism.

cell biology↗

bioRxiv2021

When development is constantly but weakly perturbed - Canalization by microRNAs

Recent studies have increasingly pointed to microRNAs (miRNAs) as the agent of GRN (gene regulatory network) stabilization as well as developmental canalization against constant but small environmental perturbations. Since the complete removal of miRNAs is lethal, we construct a Dicer-1 knockdown line (dcr-1 KD) in Drosophila that modestly reduces all miRNAs. We hypothesize that flies with modest miRNA reductions will gradually deviate from the developmental norm, resulting in late-stage failures such as shortened longevity. In the optimal culture condition, the survival to adulthood is indeed normal in the dcr-1 KD line but, importantly, adult longevity is reduced by [~] 90%. When flies are stressed by high temperature, dcr-1 KD induces lethality earlier in late pupation and, as the perturbations are shifted earlier, the affected stages are shifted correspondingly. We further show that the developmental failure is associated with GRN aberration in the larval stages even before phenotypic aberrations become observable. Hence, in late stages of development with deviations piling up, GRN would be increasingly in need of stabilization. In conclusion, miRNAs appear to be the genomes solution to weak but constant environmental perturbations.

molecular biology↗

bioRxiv2021

Engineered AIM-based Selective Autophagy to Degrade Proteins and Organelles

Techniques for disrupting of protein function are essential for biological researches and therapeutics development. Though well-established, genetic perturbation strategies may have off-target effects and/or trigger compensatory mechanisms, and cannot efficiently eliminate existing protein variants or aggregates1, 2. Therefore, precise and direct protein-targeting methods are highly desired. Here we describe a novel method for targeted protein clearance by engineering an autophagy receptor with a binder to provide target specificity and an ATG8-binding motif (AIM) to link the targets to nascent autophagosomes, thus harnessing the autophagy machinery for degradation. We demonstrate its specificity and broad potentials by degrading various fluorescent-tagged proteins and peroxisome organelle, using a tobacco-based transient expression system, and by degrading endogenous proteins in transgenic Arabidopsis expressing engineered receptors. With the wide substrate scope and specificity of selective autophagy, our method provides a convenient and robust strategy for eliminating proteins and aggregates, and may enable developing new treatments for protein-related disorders.

cell biology↗

bioRxiv2021

Quantatitive Analysis of Conserved Sites on the SARS-CoV-2 Receptor-Binding Domain to Promote Development of Universal SARS-Like Coronavirus Vaccines

Although vaccines have been successfully developed and approved against SARS-CoV-2, it is still valuable to perform studies on conserved antigenic sites for preventing possible pandemic-risk of other SARS-like coronavirus in the future and prevalent SARS-CoV-2 variants. By antibodies obtained from convalescent COVID-19 individuals, receptor binding domain (RBD) were identified as immunodominant neutralizing domain that efficiently elicits neutralizing antibody response with on-going affinity mature. Moreover, we succeeded to define a quantitative antigenic map of neutralizing sites within SARS-CoV-2 RBD, and found that sites S2, S3 and S4 (new-found site) are conserved sites and determined as subimmunodominant sites, putatively due to their less accessibility than SARS-CoV-2 unique sites. P10-6G3, P07-4D10 and P05-6H7, respectively targeting S2, S3 and S4, are relatively rare antibodies that also potently neutralizes SARS-CoV, and the last mAbs performing neutralization without blocking S protein binding to receptor. Further, we have tried to design some RBDs to improve the immunogenicity of conserved sites. Our studies, focusing on conserved antigenic sites of SARS-CoV-2 and SARS-CoV, provide insights for promoting development of universal SARS-like coronavirus vaccines therefore enhancing our pandemic preparedness.

immunology↗

bioRxiv2021

Genomic and epigenomic adaptation in SP-R210 (Myo18A) isoform-deficient macrophages

1Macrophages play fundamental roles in regulation of inflammatory responses to pathogens, resolution of inflammation and tissue repair, and maintenance of tissue homeostasis. The long (L) and short (S) isoforms of SP-R210/MYO18A, a macrophage receptor for surfactant protein A (SP-A) and C1q, regulate basal and inflammatory macrophage phenotype at multiple gene expression, translational, and subcellular levels in addition to their SP-A and C1q-mediated functions; disruption of L renders macrophages hyper-inflammatory, although the underlying mechanism had previously been unexplored. We asked whether disruption of the L isoform led to the hyper-inflammatory state via alteration of global genomic responses. RNA sequencing analysis of SP-R210L(DN) macrophages revealed basal and influenza induced upregulation of genes associated with inflammatory pathways, including TLR, RIG-I, NOD, and cytoplasmic DNA signaling, whereas knockdown of both SP-R210 isoforms (L and S) only resulted in increased RIG-I and NOD signaling. Chromatin immunoprecipitation sequencing (ChIP-seq) analysis showed increased genome-wide deposition of the pioneer transcription factor PU.1 in SP-R210L(DN) compared to WT cells. ChIP-seq analysis of histone H3 methylation showed alterations in both repressive (H3K9me3 and H3K27me3) and transcriptionally active (H3K9me3) histone marks. Influenza A virus (IAV) infection, which stimulates an array of cytosolic and TLR-mediated antiviral mechanisms, resulted in differential redistribution between proximal promoter and distal sites and decoupling of PU.1 binding from Toll-like receptor regulated gene promoters in SP-R210L(DN) cells. Our findings suggest that SP-R210L-deficient macrophages are poised with an open PU.1-primed chromatin conformation to rapidly respond to inflammatory and metabolic stimuli.

immunology↗

bioRxiv2021

Exploiting marker genes for robust classification and characterization of single-cell chromatin accessibility

MotivationSingle-cell Assay for Transposase Accessible Chromatin using sequencing (scATAC-seq) is a valuable resource to learn cis-regulatory elements such as cell-type specific enhancers and transcription factor binding sites. However, cell-type identification of scATAC-seq data is known to be challenging due to the heterogeneity derived from different protocols and the high dropout rate. ResultsIn this study, we perform a systematic comparison of 7 scATAC-seq datasets of mouse brain to benchmark the efficacy of neuronal cell-type annotation from gene sets. We find that redundant marker genes give a dramatic improvement for a sparse scATAC-seq annotation across the data collected from different studies. Interestingly, simple aggregation of such marker genes achieves performance comparable or higher than that of machine-learning classifiers, suggesting its potential for downstream applications. Based on our results, we reannotated all scATAC-seq data for detailed cell types using robust marker genes. Their meta scATAC-seq profiles are publicly available at https://gillisweb.cshl.edu/Meta_scATAC. Furthermore, we trained a deep neural network to predict chromatin accessibility from only DNA sequence and identified key motifs enriched for each neuronal subtype. Those predicted profiles are visualized together in our database as a valuable resource to explore cell-type specific epigenetic regulation in a sequence-dependent and -independent manner. Contactjesse.gillis@utoronto.ca Supplementary informationSupplementary data are available at xxxxxx online. Key pointsO_LI7 scATAC-seq datasets of mouse brain are systematically compared to benchmark the efficacy of neuronal cell-type annotation from gene sets. C_LIO_LIRedundant marker genes give a dramatic improvement for a sparse scATAC-seq annotation beyond the heterogeneity of scATAC-seq data. C_LIO_LIWe reannotated all scATAC-seq data for detailed cell types using robust marker genes and their meta scATAC-seq profiles are publicly available at a new Meta scATAC-seq server. C_LIO_LIPredicted profiles from only DNA sequence using a deep neural network are visualized together to explore sequence-dependent and -independent epigenetic regulation. C_LI

bioinformatics↗

bioRxiv2021

Deep learning from multiple experts improves identification of amyloid neuropathologies

Pathologists can label pathologies differently, making it challenging to yield consistent assessments in the absence of one ground truth. To address this problem, we present a DL approach that draws on a cohort of experts, weighs each contribution, and is robust to noisy labels. We collected 100,495 annotations on 20,099 candidate amyloid beta neuropathologies (cerebral amyloid angiopathy (CAA), and cored and diffuse plaques) from three institutions, independently annotated by five experts. DL methods trained on a consensus-of-two strategy yielded 12.6-26% improvements by area under the precision recall curve (AUPRC) when compared to those that learned individualized annotations. This strategy surpassed individual-expert models, even when unfairly assessed on benchmarks favoring them. Moreover, ensembling over individual models was robust to hidden random annotators. In blind prospective tests of 52,555 subsequent expert-annotated images, the models labeled pathologies like their human counterparts (consensus model AUPRC=0.74 cored; 0.69 CAA). This study demonstrates a means to combine multiple ground truths into a common-ground DL model that yields consistent diagnoses informed by multiple and potentially variable expert opinion.

pathology↗

bioRxiv2021

An exon junction complex-independent function of Barentsz in neuromuscular synapse growth

The exon junction complex controls the translation, degradation and localization of spliced mRNAs, and three of its four core subunits also play a role in splicing. Here we show that the fourth subunit, Barentsz, has distinct biological functions within and separate from the exon junction complex in neuromuscular development. Barentsz controls the distribution of mitochondria in larval muscles, a function that also depends on other subunits of the exon junction complex and that is not rescued by a transgene in which residues required for binding to the core subunit eIF4AIII are mutated. In contrast, interactions with the exon junction complex are not required for Barentsz to promote the growth of neuromuscular synapses. We found that the Activin ligand Dawdle shows reduced expression in barentsz mutants and acts downstream of Barentsz to control synapse growth. Both barentsz and dawdle are required in motor neurons, muscles and glia for normal synapse growth, and exogenous Dawdle can rescue synapse growth in the absence of barentsz. These results identify a biological function for Barentsz that is independent of the exon junction complex.

developmental biology↗