Biology subjects

Sun, B.

Publications and source records attributed to Sun, B..

At least 91 records · Page 5Linked to original sources

bioRxiv2022

Collagen remodeling dictates pancreatic cancer bioenergetics and outcome through DDR1 activation or degradation

Pancreatic ductal adenocarcinoma (PDAC) is a highly desmoplastic, aggressive cancer that frequently progresses by liver metastasis1. Cancer-associated fibroblasts (CAF), extracellular matrix (ECM), and type I collagen (Col I) support2-5 or restrain PDAC progression and may impede blood supply and nutrient availability6-8. The dichotomous role of the stroma in PDAC, and the mechanisms through which it influences patient survival and enables desmoplastic cancers escape nutrient limitation remain poorly understood. Here we show that matrix metalloprotease (MMP)-cleaved or intact Col I (cCol I and iCol I, respectively) exert opposing effects on PDAC bioenergetics, macropinocytosis (MP), tumor growth and liver metastasis. While cCol I activates DDR1 (discoidin domain receptor-1)-NF-{kappa}B-p62-NRF2 signaling to promote PDAC growth, iCol I triggers DDR1 degradation and restrains PDAC growth. Patients whose tumors are enriched in iCol I and low in DDR1 and NRF2 have improved median survival compared to those enriched in cCol I, DDR1 and NRF2. Inhibition of DDR1-stimulated NF-{kappa}B or mitochondrial biogenesis blocked tumorigenesis in wildtype mice but not in mice expressing MMP-resistant Col I. In summary, the diverse effects of tumor stroma on PDAC growth, metastasis, and patient survival are mediated through the Col I-DDR1-NF-{kappa}B-NRF2-mitochondrial biogenesis pathway, presenting multiple new opportunities for PDAC therapy.

cancer biology↗

bioRxiv2022

Neuronal miR-138 represses HSV-2 lytic infection by regulating viral and host genes with mechanistic differences compared to HSV-1

Herpes simplex virus 2 (HSV-2) establishes latent infection in dorsal root ganglion (DRG) neurons after productive (lytic) infection in peripheral tissues. A neuron-specific microRNA, miR-138, favors HSV-1 latency by repressing viral ICP0, and host Oct-1 and Foxc1 genes, yet the role of miR-138 in HSV-2 infection was unknown. The ICP0 mRNAs of HSV-1, HSV-2 and chimpanzee herpesvirus each have one to two canonical miR-138 binding sites. The sites are 100% conserved in 308 HSV-1 and 300 HSV-2 published sequences of clinical isolates. In co-transfection assays, miR-138 repressed HSV-2 ICP0 expression through the seed region and surrounding interactions that are different from HSV-1. An HSV-2 mutant with disrupted miR-138 binding sites on ICP0 showed increased ICP0 expression in Neuro-2a cells. Photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation confirmed miR-138 binding to HSV-2 ICP0, and identified UL19 and UL20 as additional targets, whose expression was repressed by miR-138 during co-transfection. In Neuro-2a cells, transfected miR-138 and its antagomir decreased and increased HSV-2 replication, respectively, and knockout experiment showed that miR-138s host targets OCT-1 and FOXC1 were important for HSV-2 replication. In primary mouse DRG neurons, both ICP0 and FOXC1 positively regulated HSV-2 replication, but both overexpressed and endogenous miR-138 suppressed HSV-2 replication primarily by repressing ICP0 expression. Thus, miR-138 can suppress HSV-2 neuronal replication through multiple viral and host pathways. These results reveal functional similarities and mechanistic differences in how miR-138 regulates HSV-1 and HSV-2 infection and indicate an evolutionary advantage of using miR-138 to repress lytic infection in neurons. ImportanceHerpes simplex virus 1 (HSV-1) and HSV-2 are closely related viruses with major differences. Both viruses establish latency in neurons from which they reactivate to cause disease. A key aspect of HSV latency is repression of productive infection in neurons. Based on previous work with HSV-1, we investigated the role of a neuron-specific microRNA, miR-138, in HSV-2 infection, and established it as a repressor of HSV-2 productive infection in neuronal cells. This repression is mediated mainly by targeting viral ICP0 and host Foxc1 mRNAs, but other pathways also contribute. Despite functional conservation of the role of miR-138 between HSV-1 and HSV-2, many molecular mechanisms differ including how miR-138 represses ICP0 expression and miR-138 targeting of HSV-2 but not HSV-1 UL19 and UL20. To our knowledge, this study provides the first example of host microRNA regulation of HSV-2 infection.

microbiology↗

bioRxiv2022

The m6A writer FIONA1 methylates the 3'UTR of FLC and controls flowering in Arabidopsis

Adenosine bases of RNA can be transiently modified by the deposition of a methyl-group to form N6-methyladenosine (m6A). This adenosine-methylation is an ancient process and the enzymes involved are evolutionary highly conserved. A genetic screen designed to identified suppressors of late flowering transgenic Arabidopsis plants overexpressing the miP1a microProtein yielded a new allele of the FIONA1 (FIO1) m6A-methyltransferase. To characterize the early flowering phenotype of fio1 mutant plants we employed an integrative approach of mRNA-seq, Nanopore direct RNA-sequencing and meRIP-seq to identify differentially expressed transcripts as well as differentially methylated mRNAs. We provide evidence that FIO1 is the elusive methylase responsible for the 3-end methylation of the FLOWERING LOCUS C (FLC) transcript. Furthermore, our genetic and biochemical data suggest that 3-methylation stabilizes FLC mRNAs and non-methylated FLC is a target for rapid degradation.

plant biology↗

bioRxiv2022

A role for Lin28a in aging-associated decline of adult hippocampal neurogenesis

Hippocampal neurogenesis declines with aging. Wnt ligands and antagonists within the hippocampal neurogenic niche regulate the proliferation of neural progenitor cells and the development of new neurons, and the changes of their levels in the niche mediate aging-associated decline of neurogenesis. We found that RNA-binding protein Lin28a remained existent in neural progenitor cells and granule neurons in the adult hippocampus, and decreased with aging. Loss of Lin28a inhibited the responsiveness of neural progenitor cells to niche Wnt agonist and reduced neurogenesis, thus impairing pattern separation. Overexpression of Lin28a increased the proliferation of neural progenitor cells, promoted the functional integration of newborn neurons, restored neurogenesis in Wnt-deficient dentate gyrus, and rescued the impaired pattern separation in aging mice. Our data suggest that Lin28a regulates adult hippocampal neurogenesis as an intracellular mechanism by responding to niche Wnt signals, and its decrease is involved in aging-associated decline of hippocampal neurogenesis as well as related cognitive functions.

neuroscience↗

bioRxiv2021

The Flowering Repressor SVP recruits the TOPLESS co-repressor to control flowering in chrysanthemum and Arabidopsis

Plant flowering time is a consequence of the perception of environmental and endogenous signals. The MCM1-AGAMOUSDEFICIENS-SRF-box (MADS-box) gene SHORT VEGETATIVE PHASE (SVP) is a pivotal repressor that negatively regulates the floral transition during the vegetative phase. The transcriptional corepressor TOPLESS (TPL) plays critical roles in many aspects of plant life. An interaction first identified between the second LXLXLX motif (LRLGLP) of CmSVP with CmTPL1-2, which can repress the expression of a key flowering factor CmFTL3 by binding its promotor CArG element in chrysanthemum. Genetic analysis suggested that the CmSVP-CmTPL1-2 transcriptional complex is a prerequisite for SVP to act as a floral repressor, which reduces CmFTL3 transcriptional activity. CmSVP rescued the phenotype of the svp-31 mutant in Arabidopsis, and overexpression of AtSVP or CmSVP in the Arabidopsis dominant negative mutation tpl-1 led to a loss-of-function in late flowering, which confirmed the highly conserved function of SVP in the two completely different species. Thus, we have validated a conserved machinery wherein SVP relies on TPL to inhibit flowering through the direct regulation of FT, which is more meaningful for the evolution of species and could be translated to high-quality cultivation and breeding of crops.

plant biology↗

bioRxiv2021

Three-dimensional Cancer Cell Migration Directed by Dual Mechanochemical Guidance

Directed cell migration guided by external cues plays a central role in many physiological and pathophysiological processes. The microenvironment of cells often simultaneously contains various cues and the motility response of cells to multiplexed guidance is poorly understood. Here we combine experiments and mathematical models to study the three-dimensional migration of breast cancer cells in the presence of both contact guidance and a chemoattractant gradient. We find that the chemotaxis of cells is complicated by the presence of contact guidance as the microstructure of extracellular matrix (ECM) vary spatially. In the presence of dual guidance, the impact of ECM alignment is determined externally by the coherence of ECM fibers, and internally by cell mechanosensing Rho/Rock pathways. When contact guidance is parallel to the chemical gradient, coherent ECM fibers significantly increase the efficiency of chemotaxis. When contact guidance is perpendicular to the chemical gradient, cells exploit the ECM disorder to locate paths for chemotaxis. Our results underscores the importance of fully characterizing the cancer cell microenvironment in order to better understand invasion and metastasis.

biophysics↗

bioRxiv2021

Mouse Organ Specific Proteins and Functions

Organ specific proteins (OSPs) possess great medical potentials both in clinics and in biomedical research. Applications of them -- such as alanine transaminase, aspartate transaminase, and troponins -- in clinics have raised certain concerns of their organ specificity. The dynamics and diversity of protein expression in heterogeneous human population are well known, yet their effects on OSPs are less addressed. Here we use mouse as a model and implemented a scheme of breadth study to examine the pan-organ proteome for potential variations of organ specificity in different genetic backgrounds. Using reasonable resources, we generated pan-organ proteomes of four in-bred mouse strains. The results revealed a large diversity that is more profound among OSPs than the overall proteomes. We defined a robustness score to quantify such variation and derived three sets of OSPs with different stringencies. In the meantime, we found that the enriched biological functions of OSPs are also organ specific that are sensitive and useful to assess the quality of OSPs. We hope our breadth study can open doors to explore the molecular diversity and dynamics of organ specificity at the protein level.

genomics↗

bioRxiv2021

Correlation analysis among single nucleotide polymorphisms in thirteen language genes and culture/education parameters from twenty-six countries

Language is a vital feature of any human culture, but whether language gene polymorphisms have meaningful correlations with some cultural characteristics during the long-run evolution of human languages largely remains obscure (uninvestigated). This study would be an endeavor example to find evidences for the above questions answer. In this study, the collected basic data include 13 language genes and their randomly selected 111 single nucleotide polymorphisms (SNPs), SNP profiles, 29 culture/education parameters, and estimated cultural context values for 26 representative countries. In order to undertake principal component analysis (PCA) for correlation search, SNP genotypes, cultural context and all other culture/education parameters have to be quantitatively represented into numerical values. Based on the above conditions, this study obtained its preliminary results, the main points of which contain: (1) The 111 SNPs contain several clusters of correlational groups with positive and negative correlations with each other; (2) Low cultural context level significantly influences the correlational patterns among 111 SNPs in the principal component analysis diagram; and (3) Among 29 culture/education parameters, several basic characteristics of a language (the numbers of alphabet, vowel, consonant and dialect) demonstrate least correlations with 111 SNPs of 13 language genes.

evolutionary biology↗

bioRxiv2021

Comparative genomic and pan-genomic characteristion of Staphylococcus epidermidis from different sources unveils the molecular basis and potential biomarkers of pathogenic strains

Coagulase-negative Staphylococcus (CoNS) is the most common pathogen causing traumatic endophthalmitis, Staphylococcus epidermidis is the most common species which colonizes human skin, eye surfaces and nasal cavity and is the main cause of nosocomial infection, specially foreign body-related bloodstream infections (FBR-BSIs). Although some studies have reported the genome characteristics of S. epidermidis, a comprehensive understanding of its pathogenicity and the genome of ocular trauma-sourced strains is still lacking. In this study, we sequenced, analyzed and reported the whole genomes of 11 ocular trauma-sourced samples of S. epidermidis that caused traumatic endophthalmitis. By integrating publicly available genomes, we obtained a total of 187 S. epidermidis samples from healthy and diseased eyes, skin, respiratory tract and blood. Combined with pangenome, phylogenetic and comparative genomic analyses, our study supported that S. epidermidis, regardless of niche source, exhibits two founder lineages with different pathogenicities. Moreover, we identified potential biomarkers associated with the virulence of S. epidermidis, namely, essD, uhpt, sdrF, sdrG, fbe and icaABCDR. The essD and uhpt genes have high homology with esaD and hpt in Staphylococcus aureus, showing that the genomes of S. epidermidis and S. aureus may have communicated during evolution, while the sdrF, sdrG, fbe, and icaABCDR genes are related to biofilm formation. Compared to S. epidermidis from blood sources, ocular-sourced strains causing intraocular infection had no direct relationship with biofilm formation. In conclusion, this study not only provided additional data resources for studies on S. epidermidisis, but also improved understanding of the evolution and pathogenicity of different source strains. ImportantsIn this study, we comprehensively analysied and reported the whole genome sequence (WGS) of the strains that caused traumatic endophthalmitis. Through comparative genomic analyses among 187 S. epidermidis samples from healthy and diseased eyes, skin, respiratory tract and blood, we identified 10 potential biomarkers of pathogenic strains. Finally, we revealed S. epidermidis-induced traumatic endophthalmitis may be independent of biofilm formation. Overall, our data may facilitate comparative research of S. epidermidis and provide clinical value for identifying pathogenic or contaminating strains.

microbiology↗

bioRxiv2021

Functional coupling of TRPM2 and NMDARs exacerbates excitotoxicity in ischemic brain injury

Excitotoxicity caused by NMDA receptors (NMDARs) is a major cause of neuronal death in ischemic stroke. However, past efforts of directly targeting NMDARs have unfortunately failed in clinical ischemic stroke trials. Here we reveal an unexpected mechanism underlying NMDARs-mediated neurotoxicity, which leads to identification of a novel target and development of an effective therapeutic peptide for ischemic stroke. We show that NMDARs excitotoxicity upon ischemic insults is mediated by physical and functional coupling to TRPM2. The physical interaction of TRPM2 with NMDARs results in markedly increase in the surface expression of NMDARs, leading to enhanced NMDAR function and increased neuronal death. We identified a specific NMDAR-interacting domain on TRPM2, and developed a cell-permeable peptide to uncouple TRPM2-NMDARs. The disrupting-peptide protects neurons against ischemic injury in vitro and protects mice against ischemic stroke in vivo. These findings provide an unconventional strategy to eliminate excitotoxic neuronal death without directly targeting NMDARs. HIGHLIGHTSO_LITRPM2 physically and functionally interacts with NMDARs C_LIO_LIInteraction of TRPM2 with NMDARs exacerbates NMDARs extrasynaptic excitotoxicity by increasing NMDARs surface expression during ischemic injury C_LIO_LITRPM2 recruits PKC{gamma} to the interacting complexes to increase NMDARs surface expression C_LIO_LIUncoupling the interaction between TRPM2 and NMDARs with a disrupting peptide (TAT-EE3) protects neurons against ischemic stroke in vitro and in vivo C_LI GRAPHIC ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=175 HEIGHT=200 SRC="FIGDIR/small/454247v1_ufig1.gif" ALT="Figure 1"> View larger version (53K): org.highwire.dtl.DTLVardef@e618c5org.highwire.dtl.DTLVardef@646350org.highwire.dtl.DTLVardef@b4478corg.highwire.dtl.DTLVardef@1c5742f_HPS_FORMAT_FIGEXP M_FIG C_FIG TRPM2 excerbates NMDARs excitotoxicity by physically and functionally interacting with NMDARs. The disrupting pipette TAT-EE3 protects neurons against ischemic injury in vitro and in vivo.

neuroscience↗

bioRxiv2021

Systematic analysis of the R2R3-MYB family of transcription factors in Camellia sinensis: evidence for species-specific catechin biosynthesis regulation

The R2R3-MYB transcription factor family regulates metabolism of phenylpropanoids in various plant lineages. Species-expanded or specific MYB transcription factors may regulate species-specific metabolite biosynthesis including phenylpropanoid-derived bioactive products. C. sinensis produces an abundance of specialized metabolites, which makes it an excellent model for digging into the genetic regulation of plant-specific metabolite biosynthesis. The most abundant health-promoting metabolites in tea are galloylated catechins, and the most bioactive of the galloylated catechins, epigallocatechin gallate (EGCG), is exclusively found in C. sinensis. However, the transcriptional regulation of galloylated catechin biosynthesis remains elusive. This study mined the R2R3-MYB transcription factors associated with galloylated catechin biosynthesis in C. sinensis. A total of 118 R2R3-MYB proteins, classified into 38 subgroups, were identified. R2R3-MYB subgroups specific to or expanded in C. sinensis were hypothesized to be essential to evolutionary diversification of tea-specific metabolites. Notably, nine of these R2R3-MYB genes were expressed preferentially in apical buds and young leaves, exactly where galloylated catechins accumulate. Three putative R2R3-MYB genes displayed strong correlation with key galloylated catechin biosynthesis genes, suggesting a role in regulating biosynthesis of epicatechin gallate (ECG) and EGCG. Overall, this study paves the way to reveal the transcriptional regulation of galloylated catechins in C. sinensis.

plant biology↗

bioRxiv2021

Previously unrecognized non-reproducible antibody-antigen interactions and their implications for diagnosis of viral infections including COVID-19

Antibody-antigen (Ab-Ag) interactions are canonically described by a model which exclusively accommodates non-interaction (0) or reproducible-interaction (RI) states, yet this model is inadequate to explain often-encountered non-reproducible signals. Here, by monitoring diverse experimental systems and confirmed COVID-19 clinical sera using a peptide microarray, we observed that non-specific interactions (NSI) comprise a substantial proportion of non-reproducible antibody-based results. This enabled our discovery and capacity to reliably identify non-reproducible Ab-Ag interactions (NRI), as well as our development of a powerful explanatory model ("0-RI-NRI-Hook four-state model") that is [mAb]-dependent, regardless of specificity, which ultimately shows that both NSI and NRI are not predictable yet certain-to-happen. In experiments using seven FDA-approved mAb drugs, we demonstrated the use of NSI counts in predicting epitope type. Beyond challenging the centrality of Ab-Ag interaction specificity data in serology and immunology, our discoveries also facilitated the rapid development of a serological test with uniquely informative COVID-19 diagnosis performance.

immunology↗

bioRxiv2021

The noncoding RNA PRANCR regulates splicing of Fibronectin-1 to control keratinocyte proliferation and migration

Most human genes undergo alternative splicing (AS), but the regulation and functional consequences of most splicing events remain unknown. Long noncoding RNAs (lncRNAs) have recently been discovered to have novel roles in the regulation of AS. Here we investigate whether PRANCR, a lncRNA recently identified to be essential for epidermis formation, functions by controlling AS of cell fate genes. Using transcriptome-wide analysis, we identified 238 exonic splicing events regulated by PRANCR. Among these is alternative splicing of an exon containing the extra domain A (EDA) in the gene fibronectin-1 (FN1). Expression of the FN1-EDA+ isoform is enriched in proliferating keratinocytes. We find that PRANCR regulates EDA inclusion by controlling expression of the serine/arginine-rich splicing factors (SRSFs) 1 and 7. Depletion of PRANCR or FN1-EDA resulted in decreased proliferation, increased CDKN1A/p21, and inhibition of keratinocyte migration. We find that these cellular phenotypes can be explained by reduced phosphorylation of focal adhesion kinase (FAK). Collectively, these results identify a lncRNA regulating skin function through alternative splicing of a cell fate gene.

cell biology↗

bioRxiv2021

Purinoreceptors and ectonucleotidases control ATP-induced calcium waveforms and calcium-dependent responses in microglia

1Adenosine triphosphate (ATP) drives microglia motility and cytokine production by activating P2X- and P2Y- class purinergic receptors with extracellular ATP and its metabolites. Purinergic receptor activation gives rise to diverse intracellular Ca2+ signals, or waveforms, that differ in amplitude, duration, and frequency. Whether and how these diverse waveforms influence microglia function is not well established. We developed a computational model trained with published primary murine microglia studies. We simulate how purinoreceptors influence Ca2+ signaling and migration and how purinoreceptor expression modifies these processes. Our simulation confirmed that P2 receptors encode the amplitude and duration of the ATP-induced calcium waveforms. Our simulations also implicate CD39, an ectonucleotidase that rapidly degrades ATP, as a regulator of purinergic receptor-induced Ca2+ responses. We, therefore, next evaluated how purinoreceptors and ectonucleotidase work in tandem. Our modeling results indicate that small transients are sufficient to promote motility, while large and sustained transients are needed for cytokine responses. Lastly, we predict how these phenotypical responses vary in a BV2 microglia cell line using published P2 receptor mRNA data to illustrate how our computer model can be extrapolated to diverse microglia subtypes. These findings provide important insights into how differences in purinergic receptor expression influence the microglias responses to ATP.

physiology↗

bioRxiv2021

The non-canonical interaction between calmodulin and calcineurin contributes to the differential regulation of plant-derived calmodulins on calcineurin.

Calmodulin (CaM) is an important Ca2+ signaling hub that regulates many protein signaling pathways. In recent years, several CaM homologs expressed in plants have been shown to regulate mammalian targets and they are attractive for gene therapy. However, the molecular basis of how the CaM homologs mutations impact target activation is unclear, which limits efforts to engineer their functional properties. To understand these mechanisms, we examined two CaM isoforms found in soybean plants that differentially regulate a mammalian target, calcineurin (CaN). These CaM isofroms, sCaM-1 and sCaM-4 share >90% and ~ 78% identity with the mammalian CaM (mCaM), respectively, activate CaN with comparable or reduced activity relative to mCaM. We used molecular simulations and experimental assays to probe whether calcium and protein-protein binding interactions are altered in plant CaMs relative to mCaM as a basis for differential CaN regulations. We found that the two sCaMs Ca2+-binding properties such as coordination and affinity are comparable to mCaM. Further, the binding of CaM to the CaM binding region (CaMBR) in CaN is also comparable among the three CaMs, as evidenced by calculated binding free energies and experimental measured EC50 [CaM]. However, mCaM and sCaM-1 exhibited stronger binding with a secondary region of CaNs regulatory domain that is weakened for sCaM-4. This secondary interaction is likely to affect the turnover rate (kcat) of CaN based on our modeling of enzyme activity and is consistent with our experimental data. Together, our data show how plant-derived CaM variants can alter target activation through interactions beyond Ca2+-binding and canonical CaMBR binding, which may extend beyond the mammalian CaN target.

biochemistry↗

bioRxiv2021

Evolutionary insights into a non-coding deletion of SARS-CoV-2 B.1.1.7

Three prevalent SARS-CoV-2 Variants of Concern (VOCs) were emerged and caused epidemic waves. It is essential to uncover the key genetic changes that cause the high transmissibility of VOCs. However, different viral mutations are generally tightly linked so traditional population genetic methods may not reliably detect beneficial mutation. In this study, we proposed a new pandemic-scale phylogenomic approach to detect mutations crucial to transmissibility. We analyzed 3,646,973 high-quality SARS-CoV-2 genomic sequences and the epidemiology metadata. Based on the sequential occurrence order of mutations and the instantaneously accelerated furcation rate, the analysis revealed that two non-coding mutations at the position of 28271 (g.a28271-/t) might be crucial for the high transmissibility of Alpha, Delta and Omicron VOCs. Both two mutations cause an A-to-T change at the core Kozak site of the N gene. The analysis also revealed that the non-coding mutations (g.a28271-/t) alone are unlikely to cause high viral transmissibility, indicating epistasis or multilocus interaction in viral transmissibility. A convergent evolutionary analysis revealed that g.a28271-/t, S:P681H/R and N:R203K/M occur independently in the three-VOC lineages, suggesting a potential interaction among these mutations. Therefore, this study unveils that non-synonymous and non-coding mutations could affect the transmissibility synergistically.

evolutionary biology↗

bioRxiv2021

Dynamic phase separation of the androgen receptor and its coactivators to regulate gene expression.

Numerous cancers, including prostate cancer (PCa), are addicted to transcription programs driven by superenhancers (SEs). The transcription of genes at SEs is enabled by the formation of phase-separated condensates by transcription factors and co-activators with intrinsically disordered regions. The androgen receptor (AR), main oncogenic driver in PCa, contains large disordered regions and is co-recruited with the co-activator MED1 to SEs to promote oncogenic programs. In this work, we show that dynamic AR-rich, liquid-like foci form in PCa models upon androgen stimulation and correlate with AR transcriptional activity. The co-activator MED1 plays an essential role in the formation of AR foci while AR antagonists hinder their formation. These results suggest that enhanced compartmentalization of AR and co-activators at SEs may play an important role in the activation of oncogenic transcription programs in PCa. A better understanding of the assembly and the regulation of these AR-rich compartments may provide novel therapeutic options.

cancer biology↗

bioRxiv2021

fmr1 mutation interacts with sensory experience to alter the early development of behavior and sensory coding in zebrafish

While Autism Spectrum Disorders (ASDs) are developmental in origin little is known about how they affect the early development of behavior and sensory coding, or how this is modulated by the sensory environment. The most common inherited form of autism is Fragile X syndrome, caused by a mutation in FMR1. Here we show that zebrafish fmr1-/- mutant larvae raised in a naturalistic visual environment display early deficits in hunting behavior, tectal map development, tectal network properties and decoding of spatial stimuli. However when given a choice they preferred an environment with reduced visual stimulation, and rearing them in this environment improved these metrics. Older fmr1-/- fish showed differences in social behavior, spending more time observing a conspecific, but responding more slowly to social cues. Together these results help reveal how fmr1-/- changes the early development of vertebrate brain function, and how manipulating the environment could potentially help reduce these changes.

neuroscience↗