SEARCH · bioRxiv Science

Results for “Developmental Biology”

Search indexed bioRxiv preprints in genomics, neuroscience, cell biology and bioinformatics. Read source abstracts and check manuscript versions; preprints are not peer reviewed.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 775 records · Page 43Linked to original sources

bioRxiv2018

Bone Morphology is Regulated Modularly by Global and Regional Genetic Programs

During skeletogenesis, a variety of protrusions of different shapes and sizes develop on the surfaces of long bones. These superstructures provide stable anchoring sites for ligaments and tendons during the assembly of the musculoskeletal system. Despite their importance, the mechanism by which superstructures are patterned and ultimately give rise to the unique morphology of each long bone is far from understood. In this work, we provide further evidence that long bones form modularly from Sox9+ cells, which contribute to their substructure, and from Sox9+/Scx+ progenitors that give rise to superstructures. Moreover, we identify components of the genetic program that controls the patterning of Sox9+/Scx+ progenitors and show that this program includes both global and regional regulatory modules.\n\nUsing light sheet fluorescence microscopy combined with genetic lineage labeling, we mapped the broad contribution of the Sox9+/Scx+ progenitors to the formation of bone superstructures. Additionally, by combining literature-based evidence and comparative transcriptomic analysis of different Sox9+/Scx+ progenitor populations, we identified genes potentially involved in patterning of bone superstructures. We present evidence indicating that Gli3 is a global regulator of superstructure patterning, whereas Pbx1, Pbx2, Hoxa11 and Hoxd11 act as proximal and distal regulators, respectively. Moreover, by demonstrating a dose-dependent pattern regulation in Gli3 and Pbx1 compound mutations, we show that the global and regional regulatory modules work coordinately. Collectively, our results provide strong evidence for genetic regulation of superstructure patterning that further supports the notion that long bone development is a modular process.

developmental biology↗

bioRxiv2018

Presence of midline cilia supersedes the expression of Lefty1 in forming the midline barrier during the establishment of left-right asymmetry

Cilia in the vertebrate left-right organizer are required for the original break in left-right (L-R) symmetry. Subsequently, proper L-R patterning relies on asymmetric expression of Nodal in the lateral plate mesoderm (LPM). Lefty1, expressed in the embryonic midline, has been defined as the midline barrier, restricting the expression of Nodal to the left LPM. Here we use the mouse ciliary transition zone mutant Mks1krc that has left isomerism and bilateral expression of the NODAL target Pitx2, to reveal that the expression of Lefty1 in the midline is insufficient for the establishment of the midline barrier. We further show through a comparison of two Tmem107 mutants that cilia in the midline are required to supplement Lefty1 expression and establish the functional midline barrier. Tmem107null mutants have no cilia in the midline and display left isomerism due to the loss of the midline barrier, whereas Tmem107schlei hypomorphic mutants have numerous cilia in the node and the midline, leading to normal Lefty1 expression and L-R patterning. This study reveals a novel role for cilia in the maintenance of L-R asymmetry.

developmental biology↗

bioRxiv2018

Generation of the squamous epithelial roof of the 4th ventricle

We use the transparency of zebrafish embryos to reveal the de novo generation of a simple squamous epithelium and identify the cellular architecture in the epithelial transition zone that ties this squamous epithelium to the columnar neuroepithelium within the embryos brain. The simple squamous epithelium of the rhombencephalic roof plate is pioneered by distinct mesenchymal cells at the dorsal midline of the neural tube. Subsequently a progenitor zone is established at the interface between columnar epithelium of the rhombic lip and the expanding squamous epithelium of the roof plate. Surprisingly this interface consists of a single progenitor cell type that we have named the veil cell. Veil cells express gdf6a and constitute a lineage restricted stem zone that generates the squamous roof plate by direct transformation and asymmetrically fated divisions. Experimental restriction of roof plate expansion leads to extrusion of veil cell daughters and squamous cells, suggesting veil cell fate is regulated by the space available for roof plate growth.

developmental biology↗

bioRxiv2018

The RhoGAP myosin 9/HUM-7 integrates membrane signals to modulate Rho/RHO-1 during embryonic morphogenesis in C. elegans

During embryonic morphogenesis, cells and tissues undergo dramatic movements under the control of F-actin regulators. Our studies of epidermal cell migrations in developing C. elegans embryos have identified multiple plasma membrane signals that regulate the Rac GTPase, thus regulating WAVE and Arp2/3 complexes, to promote branched F-actin formation and polarized enrichment. We describe here a pathway that acts in parallel to Rac to transduce membrane signals to control epidermal F-actin through the GTPase Rho. Rho contributes to epidermal migrations through effects on underlying neuroblasts. Here we identify signals to regulate Rho in the epidermis. HUM-7, the C. elegans homolog of human Myo9A and Myo9B, regulates F-actin dynamics during epidermal migrations, by controlling Rho. Genetics and biochemistry support that HUM-7 behaves as GAP for the Rho GTPase, so that loss of HUM-7 enhances Rho-dependent epidermal cell behaviors. We identify SAX-3/ROBO as an upstream signal that contributes to attenuated Rho activation through its regulation of HUM-7/Myo9. These studies identify a new role for Rho during epidermal cell migrations, and suggest that Rho activity is regulated by SAX-3/ROBO acting on the RhoGAP HUM-7.

developmental biology↗

bioRxiv2018

EWSR1 affects PRDM9-dependent histone 3 methylation and provides a link between recombination hotspots and the chromosome axis

Meiotic recombination in most mammals requires recombination hotspot activation through the action of the histone 3 lysine-4 and lysine-36 methyltransferase PRDM9 to ensure successful double-strand break initiation and repair. Here we show that EWSR1, a protein whose role in meiosis was not previously clarified in detail, binds to both PRDM9 and pREC8, a phosphorylated meiosis-specific cohesin, in male meiotic cells. We created a Ewsr1 conditional knockout mouse models to deplete EWSR1 before the onset of meiosis, and found that absence of EWSR1 causes meiotic arrest with decreased histone trimethylation at meiotic hotspots, impaired DNA double-strand break repair, and reduced crossover number. Our results demonstrate that EWSR1 is essential for promoting PRDM9-dependent histone methylation and normal meiotic progress, possibly by facilitating the linking between PRDM9-bound hotspots and the nascent chromosome axis. Author SummaryIn most mammals, including humans and mice, genetic recombination initiates when the meiosis-specific protein PRDM9 binds specific DNA sequences, known as hotspots, at the beginning of the extended prophase I of meiosis, and activates them by trimethylating histone 3 at lysine-4 and lysine-36 on nearby nucleosomes. Although this activation of hotspots is believed to occur on the chromatin loops, the subsequent double-strand break formation and repair occur on a proteinaceous structure known as the chromosome axis. We now show that Ewing sarcoma RNA binding protein 1 (EWSR1) is a key player in early recombination events, binding to PRDM9, promoting PRDM9-dependent histone methylation, and facilitating the linking between PRDM9-bound hotspots and the nascent chromosome axis through the meiosis-specific cohesion REC8. As a result of these activities, EWSR1 assures sufficient numbers of properly positioned crossovers in each meiosis.

developmental biology↗

bioRxiv2018

Protective effects of low-intensity pulsed ultrasound on mandibular condylar cartilage exposed to mechanical overloading

The aim of this study was to examine the role of low-intensity pulsed ultrasound (LIPUS) exposure in the onset and early progression of temporomandibular joint (TMJ) osteoarthritis (TMJ-OA) induced by mechanical overloading. Fifteen-week-old male Wistar rats were divided into two experimental groups and a control group (n = 5 each). In the experimental groups, both TMJs were subjected to mechanical overloading by forced mouth opening using a jaw-opening device for 3 h/day for 5 continuous days. After mechanical overloading, TMJs in one experimental group were exposed to LIPUS for 20 min/day. After the experiments, mandibles were resected from the rats, and the condyles were processed. The bones were analyzed using high-resolution microcomputed tomography (micro-CT). The resected TMJs were also subjected to histological analysis and immunohistochemical staining. Micro-CT images of the mandibular condyle showed severe subchondral trabecular bone loss in the experimental group with overloading. Treatment with LIPUS after overloading resulted in decreased subchondral trabecular bone resorption. In TMJ sections from the experimental group with overloading, cell-free regions and proteoglycan loss characterized the cartilage degradation; LIPUS exposure restricted these changes in the mandibular condyle. Furthermore, the number of tartrate-resistant acid phosphatase-positive osteoclasts in the mineralized layer of the condylar cartilage increased after mechanical overloading and decreased after LIPUS treatment. Our findings suggest that LIPUS exposure after mechanical TMJ overloading downregulates subchondral trabecular bone resorption and proteoglycan loss in the mandibular condylar cartilage. Thus, it may prove to be protective effects of LIPUS exposure on onset and early progression of TMJ-OA induced by mechanical overloading.

developmental biology↗

bioRxiv2018

Regulated nuclear accumulation of a histone methyltransferase times the onset of heterochromatin formation in C. elegans embryos

Heterochromatin formation during early embryogenesis is timed precisely, but it has been elusive how this process is regulated. Here we report the discovery of a histone methyltransferase complex whose nuclear accumulation and activation establishes the onset of heterochromatin formation in C. elegans embryos. We find that the inception of heterochromatin generation coincides with the accumulation of the Histone H3 Lysine 9 (H3K9) methyltransferase MET-2 (SETDB) into nuclear hubs. The absence of MET-2 results in delayed and disturbed heterochromatin formation, whereas accelerated nuclear localization of the methyltransferase leads to precocious H3K9 methylation. We identify two factors that bind to and function with MET-2: LIN-65, which resembles ATF7IP, localizes MET-2 into nuclear hubs, and ARLE-14, orthologous to ARL14EP, promotes stable association of MET-2 with chromatin. These data reveal that nuclear accumulation of MET-2 in conjunction with LIN-65 and ARLE-14 regulates timing of heterochromatin domains during embryogenesis.\n\nONE SENTENCE SUMMARYMET-2/SETDB1 and interactors LIN-65/ATF7IP and ARLE-14/ARL14EP initiate heterochromatin formation during embryogenesis.

developmental biology↗

bioRxiv2018

Emergence of a node-like population within an in vitro derived Neural Mesodermal Progenitors (NMPs) population

The mammalian embryos Caudal Lateral Epiblast (CLE) harbours bipotent progenitors, called Neural Mesodermal Progenitors (NMPs), that contribute to the spinal cord and the paraxial mesoderm throughout axial elongation. Here we performed a single cell analysis of different in vitro NMPs populations produced either from embryonic stem cells (ESCs) or epiblast stem cells (EpiSCs) and compared them to E8.25 CLE mouse embryos. In our analysis of this region our findings challenge the notion that NMPs should coexpress Sox2 and T. We built a Support Vector Machine (SVM) based on the embryo CLE and use it as a classification model to analyse the in vitro NMP-like populations. We showed that ESCs derived NMPs are heterogeneous and contain few NMP-like cells, whereas EpiSCs derived NMPs, produce a high proportion of cells with the embryo NMP signature. Importantly, we found that the population from which the Epi-NMPs are derived in culture, contains a nodelike population, which is responsible for maintaining the expression of T in vitro. These results mimic the events in vivo and suggest a sequence of events for the NMPs emergence.

developmental biology↗

bioRxiv2018

The Drosophila SWI/SNF chromatin-remodeling complexes play separate roles in regulating growth and cell fate during regeneration

To regenerate, damaged tissue must heal the wound, regrow to the proper size, replace the correct cell types, and return to the normal gene-expression program. However, the mechanisms that temporally and spatially control the activation or repression of important genes during regeneration are not fully understood. To determine the role that chromatin modifiers play in regulating gene expression after tissue damage, we induced ablation in Drosophila imaginal wing discs, and screened for chromatin regulators that are required for epithelial tissue regeneration. Here we show that many of these genes are indeed important for promoting or constraining regeneration. Specifically, the two SWI/SNF chromatin-remodeling complexes play distinct roles in regulating different aspects of regeneration. The PBAP complex regulates regenerative growth and developmental timing, and is required for the expression of JNK signaling targets and the growth promoter Myc. By contrast, the BAP complex ensures correct patterning and cell fate by stabilizing expression of the posterior gene engrailed. Thus, both SWI/SNF complexes are essential for proper gene expression during tissue regeneration, but they play distinct roles in regulating growth and cell fate. Summary statementDuring regeneration of the Drosophila wing disc, the SWI/SNF PBAP complex is required for regenerative growth and expression of JNK signaling targets, while the BAP complex maintains posterior cell fate.

developmental biology↗

bioRxiv2018

Growth zone segmentation in the milkweed bug Oncopeltus fasciatus sheds light on the evolution of insect segmentation

One of the best studied developmental processes is the Drosophila segmentation cascade. However, this cascade is generally considered to be highly derived and unusual. We present a detailed analysis of the sequential segmentation cascade of the milkweed bug Oncopletus fasciatus, as a comparison to Drosophila, with the aim of reconstructing the evolution of insect segmentation. We analyzed the expression of 12 genes, representing different phases during segmentation. We reconstruct the spatio-temporal relationships among these genes And their roles and position in the cascade. We conclude that sequential segmentation in the Oncopeltus germband includes three phases: Primary pair-rule genes generate segmental gene expression in the anterior growth zone, followed by secondary pair-rule genes, expressed in the transition between the growth zone and the segmented germband. Segment polarity genes are expressed in the segmented germband. This process generates a single-segment periodicity, and does not have a double-segment pattern at any stage.

developmental biology↗

bioRxiv2018

Single-cell mRNA profiling reveals heterogeneous combinatorial expression of Hoxd genes during limb development

ABSTRACT (177 words)A global analysis of gene expression during development reveals specific transcription patterns associated with the emergence of various cell types, tissues and organs. These heterogeneous patterns are instrumental to ensure the proper formation of the different parts of our body, as shown by the phenotypic effects generated by functional genetic approaches. However, variations at the cellular level can be observed within each structure or organ. In the developing mammalian limbs, expression of Hoxd genes is differentially controlled in space and time in cells that will pattern the digits and the arms. Here we analyze single-cell transcriptomes of limb bud cells and show that Hox genes are expressed in specific combinations that match particular cell types. In the presumptive digits, we find that the expression of Hoxd gene is unbalanced, despite their common genomic proximity to known global enhancers, often expressing only a subset of the five genes transcribed in these cells. We also report that combinatorial expression follows a pseudo-time sequence, suggesting that a progression in combinatorial expression may be associated with cellular diversity in developing digits.\n\nHIGHLIGHTSO_LICollinear expression of Hox genes is only weaved at the tissue scale\nC_LIO_LIEnhancer-sharing to specific target genes is reduced at the single-cell level\nC_LIO_LIHoxd gene combinatorial expression is linked to distinct transcriptional signatures\nC_LIO_LIIn presumptive digits, Hoxd combinations follow a pseudotime trajectory\nC_LI

developmental biology↗

bioRxiv2018

doublesex regulates sexually dimorphic beetle horn formation by integrating spatial and temporal developmental contexts in the Japanese rhinoceros beetle Trypoxylus dichotomus

AbstractMany scarab beetles have sexually dimorphic exaggerated horns that are an evolutionary novelty. Since the shape, number, size, and location of horns are highly diverged within Scarabaeidae, beetle horns are an attractive model for studying the evolution of sexually dimorphic and novel traits. In beetles including the Japanese rhinoceros beetle Trypoxylus dichotomus, the sex determination gene doublesex (dsx) plays a crucial role in sexually dimorphic horn formation during larval-pupal development. However, knowledge of when and how dsx drives the gene regulatory network (GRN) for horn formation to form sexually dimorphic horns during development remains elusive. To address this issue, we identified a Trypoxylus-ortholog of the sex determination gene, transformer (tra), that regulates sex-specific splicing of the dsx pre-mRNA, and whose loss of function results in sex transformation. By knocking down tra function at multiple developmental timepoints during larval-pupal development, we estimated the onset when the sex-specific GRN for horn formation is driven. In addition, we also revealed that dsx regulates different aspects of morphogenetic activities during the prepupal and pupal developmental stages to form appropriate morphologies of pupal head and thoracic horn primordia as well as those of adult horns. Based on these findings, we discuss the evolutionary developmental background of sexually dimorphic trait growth in horned beetles.\n\nAuthor Summary:\n\nBeetle horns are highly enriched in a particular family Scarabaeidae, although the shape, size and number of horns are diversified within the group. In addition, many scarab beetle horns are sexually dimorphic. It has been questioned how a particular group of beetles has originated and diversified evolutionary novel horns. Here we found the exact time when morphological sexual dimorphism of horn primordia appeared, estimated the onset of the developmental program for sexually dimorphic horn formation driven by Doublesex, and revealed that Doublesex regulates different aspects of cell activities of horn primordia depending on the spatiotemporal contexts. Our study provides our understanding regarding regulatory shifts in these mechanisms during the evolution of sexually dimorphic traits in horned beetles.

developmental biology↗

bioRxiv2018

Molecular determinants of WNT9b responsiveness in nephron progenitor cells

Primed nephron progenitor cells (NPCs) appear in metanephric mesenchyme by Ell.5 and differentiate in response to the inductive WNT9b signal from the ureteric bud. However, the NPC WNT-receptor complex is unknown. We obtained M15 cells from E10.5 mesonephric mesenchyme and systematically analyzed components required for canonical WNT9b-responsiveness. When M15 cells were transfected with a ({beta}-catenin luciferase reporter plasmid, exposure to recombinant WNT9b resulted in minimal luciferase activity. We then analyzed mRNA-expression of WNT-pathway components and identified Fzdl-6 and Lrp6 transcripts but not RSPO1. When M15 cells were treated with recombinant RSPO1 the response to transfected WNT9b was augmented 4.8-fold. Co-transfection of M15 cells with Fzd5 (but no other Fzd family member) further increased the WNT9b signal to 16.8-fold and siRNA knockdown of Fzd5 reduced the signal by 52%. Knockdown of Lrp6 resulted in 60% WNT9b signal reduction. We confirmed Fzd5, Lrp6 and RSPO1 rrtRNA expression in CITED1(+) NPCs from E15.5 embryonic mouse kidney. Thus, while many WNT signaling-pathway components are present by E10.5, optimum responsiveness of Ell.5 cap mesenchyme requires that NPCs acquire RSPO1, FZD5 and LRP6.\n\nSummary StatementResponsiveness to the inductive WMT9b signal from ureteric bud is crucial for nephrogenesis. Here we analyze the molecules needed to prime nephron progenitor cells in embryonic mouse kidney.

developmental biology↗

bioRxiv2018

Genomic Analysis of a Transcriptional Networks Directing Progression of Cell States During MGE development.

BackgroundHomeodomain (HD) transcription factor (TF) NKX2-1 critical for the regional specification of the medial ganglionic eminence (MGE) as well as promoting the GABAergic and cholinergic neuron fates via the induction of TFs such as LHX6 and LHX8. NKX2-1 defines MGE regional identity in large part through transcriptional repression, while specification and maturation of GABAergic and cholinergic fates is mediated in part by transcriptional activation via TFs such as LHX6 and LHX8. Here we analyze the signaling and TF pathways, downstream of NKX2-1, required for GABAergic and cholinergic neuron fate maturation.\n\nMethodsDifferential ChIP-seq analysis was used to identify regulatory elements (REs) where chromatin state was sensitive to change in the Nkx2-1cKO MGE at embryonic day (E) 13.5. TF motifs in the REs were identified using RSAT. CRISPR-mediated genome editing was used to generate enhancer knockouts. Differential gene expression in these knockouts was analyzed through RT-qPCR and in situ hybridization. Functional analysis of motifs within hs623 was analyzed via site directed mutagenesis and reporter assays in primary MGE cultures.\n\nResultsWe identified 4782 activating REs (aREs) and 6391 repressing REs (rREs) in the Nkx2-1 conditional knockout (Nkx2-1cKO) MGE. aREs are associated with basic-Helix-Loop-Helix (bHLH) TFs. Deletion of hs623, an intragenic Tcf12 aRE, caused a reduction of Tcf12 expression in the sub-ventricular zone (SVZ) and mantle zone (MZ) of the MGE. Mutation of LHX, SOX and octamers, within hs623, caused a reduction of hs623 activity in MGE primary cultures.\n\nConclusionsTcf12 expression in the sub-ventricular zone (SVZ) of the MGE is mediated through aRE hs623. The activity of hs623 is dependent on LHX6, SOX and octamers. Thus, maintaining the expression of Tcf12 in the SVZ involves on TF pathways parallel and genetically downstream of NKX2-1.

developmental biology↗

bioRxiv2018

Molecular mechanism of symmetry breaking in a 3D model of a human epiblast

Breaking the anterior-posterior (AP) symmetry in mammals takes place at gastrulation. Much of the signaling network underlying this process has been elucidated in the mouse, however there is no direct molecular evidence of events driving axis formation in humans. Here, we use human embryonic stem cells to generate an in vitro 3D model of a human epiblast whose size, cell polarity, and gene expression are similar to a 10-day human epiblast. A defined dose of bone mor-phogenetic protein 4 (BMP4) spontaneously breaks axial symmetry, and induces markers of the primitive streak and epithelial to mesenchymal transition. By gene knockouts and live-cell imaging we show that, downstream of BMP4, WNT3 and its inhibitor DKK1 play key roles in this process. Our work demonstrates that a model human epiblast can break axial symmetry despite no asymmetry in the initial signal and in the absence of extraembryonic tissues or maternal cues. Our 3D model opens routes to capturing molecular events underlying axial symmetry breaking phenomena, which have largely been unexplored in model human systems.

developmental biology↗

bioRxiv2018

Hhex regulates the specification and growth of the hepatopancreatic ductal system

Significant efforts have advanced our understanding of foregut-derived organ development; however, little is known about the molecular mechanisms that underlie the formation of the hepatopancreatic ductal (HPD) system. Here, we report a role for the homeodomain transcription factor Hhex in directing HPD progenitor specification in zebrafish. Loss of Hhex function results in impaired HPD system formation. We found that Hhex specifies a distinct population of HPD progenitors that gives rise to the cystic duct, common bile duct, and extra-pancreatic duct. Since hhex is not uniquely expressed in the HPD region but is also expressed in endothelial cells and the yolk syncytial layer (YSL), we tested the role of blood vessels as well as the YSL in HPD formation. We found that blood vessels are required for HPD patterning, but not for HPD progenitor specification. In addition, we found that Hhex is required in both the endoderm and the YSL for HPD development. Our results shed light on the mechanisms necessary to direct endodermal progenitors towards the HPD fate and also advance our understanding of HPD system formation.

developmental biology↗

bioRxiv2018

Nr5a1 suppression during the fetal period optimizes ovarian development by fine-tuning of Notch signaling

The nuclear receptor NR5A1 (also known as Ad4BP, or SF1) is essential for the initial steps of mammalian gonadal development. The Nr5a1 gene is equally expressed in XX and XY gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in XX gonads. We recently reported a case of 46, XX disorder of sex development (DSD) in which ectopically expressed NR5A1 in XX gonads led to an ovo-testicular phenotype, suggesting that excess NR5A1 can direct the development of immature XX gonads towards testicular formation. However, a direct causal relationship has not been demonstrated in an animal model. Here, using a Wt1-BAC (bacterial artificial chromosome) transgene system, we generated two lines of mice overexpressing Nr5a1 in the fetal gonads at different levels. One of these lines (Tg-S), highly expressing Nr5a1, revealed that enforced Nr5a1 expression alone is insufficient to switch the fate of the 46,XX gonads toward testicular formation in mice. In the other line (Tg-A) expressing Nr5a1 at lower level, ovarian development was compromised, with multi-oocyte follicles, reduced number of matured follicles, and impaired expression of Wnt4, resulting in late onset infertility at 20 weeks after birth. The phenotype was similar to that of genetically modified mice with impaired Notch signaling. Indeed, the expression level of Notch2 and 3 was significantly reduced in Tg-A mice, and the ovarian phenotype in Tg-A mice was almost completely rescued by in utero treatment with a Notch2 agonist HMN2-29. We conclude that suppression of Nr5a1 during the fetal period optimizes ovarian development by fine tuning of Notch signaling levels.\n\nAUTHOR SUMMARYSexual development is a process of differentiation from undifferentiated bipotential gonads, and insight into sexual differentiation will bring important new knowledge to our understanding of organogenesis. The nuclear receptor NR5A1 which is essential for mammalian gonadal development, is equally expressed in both gonadal primordia, but after sex determination, is up-regulated in XY and down-regulated in XX gonads. We have recently demonstrated that this down-regulation is mediated by ovarian transcription factor, Forkhead box L2 (FOXL2). This finding raised two key questions, whether Nr5a1 can function as a male sex-determining factor, and whether the repression is essential for appropriate ovarian development. By generating two lines Tg mice in XX gonads with different enforced expression levels of Nr5a1, our present study revealed that alterations in Nr5a1 dosage, either reduced or excessive, result in pathological effects in ovarian development and female fertility, indicating that the precise control of Nr5a1 at the transcriptional level is essential for optimal ovarian development. We envisage that the improved understanding of how this pathway regulates ovarian development and female fertility would aid the development of artificial somatic ovarian cells, which in turn may provide a valuable treatment option in reproductive medicine.\n\nABBREVIATIONS

developmental biology↗

bioRxiv2018

Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish

Spinal cord injury leads to a massive response of innate immune cells (microglia, macrophages, neutrophils) both, in non-regenerating mammals and in successfully regenerating zebrafish, but the role of these immune cells in functional spinal cord regeneration in zebrafish has not been addressed. Here we show that inhibiting inflammation reduces and promoting it accelerates axonal regeneration in larval zebrafish. Mutant analyses show that peripheral macrophages, but not neutrophils or microglia, are necessary and sufficient for full regeneration. Macrophage-less irf8 mutants show prolonged inflammation with elevated levels of Il-1{beta} and Tnf-. Decreasing Il-1{beta} levels or number of Il-1{beta}+ neutrophils rescues functional regeneration in irf8 mutants. However, during early regeneration, interference with Il-1{beta} function impairs regeneration in irf8 and wildtype animals. Inhibiting Tnf- does not rescue axonal growth in irf8 mutants, but impairs it in wildtype animals, indicating a pro-regenerative role of Tnf-. Hence, inflammation is tightly and dynamically controlled by macrophages to promote functional spinal cord regeneration in zebrafish.

developmental biology↗