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Rxivist combines preprints from bioRxiv with data from Twitter to help you find the papers being discussed in your field. Currently indexing 89,274 bioRxiv papers from 382,705 authors.

Most downloaded bioRxiv papers, all time

in category developmental biology

2,614 results found. For more information, click each entry to expand.

1901: Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
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Posted to bioRxiv 15 Mar 2020

Gli3 utilizes Hand2 to synergistically regulate tissue-specific transcriptional networks
248 downloads developmental biology

Kelsey H Elliott, Xiaoting Chen, Joseph Salomone, Praneet Chaturvedi, Preston A Schultz, Sai K Balchand, Jeffrey D Servetas, Aimée Zuniga, Rolf Zeller, Brian Gebelein, Matthew T. Weirauch, Kevin A. Peterson, Samantha A. Brugmann

Despite a common understanding that Gli TFs are utilized to reiterate a Hh morphogen gradient, genetic analyses suggest craniofacial development does not completely fit this paradigm. We demonstrated that rather than being driven by a Hh threshold, robust Gli3 transcriptional activity during skeletal and glossal development required interaction with the bHLH TF Hand2. Not only did genetic and expression data support a co-factorial relationship, but genomic analysis further revealed that Gli3 and Hand2 were enriched at regulatory elements for genes essential for mandibular patterning and development. Interestingly, motif analysis at sites co-occupied by Gli3 and Hand2 uncovered mandibular-specific, low-affinity, 'divergent' Gli binding motifs (dGBMs). Functional validation revealed these dGBMs conveyed synergistic activation of Gli targets essential for mandibular patterning and development. In summary, this work elucidates a novel, sequence-dependent mechanism for Gli transcriptional activity within the craniofacial complex that is independent of a graded Hh signal.

1902: Hierarchical stem cell topography splits growth and homeostatic functions in the fish gill
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Posted to bioRxiv 30 Nov 2018

Hierarchical stem cell topography splits growth and homeostatic functions in the fish gill
247 downloads developmental biology

Julian Stolper, Elizabeth Ambrosio, Diana-P Danciu, David A. Elliot, Kiyoshi Naruse, Anna Marciniak-Czochra, Lazaro Centanin

While lower vertebrates contain adult stem cells (aSCs) that maintain homeostasis and drive in-exhaustive organismal growth, mammalian aSCs display mainly the homeostatic function. Understanding aSC-driven growth is of paramount importance to promote organ regeneration and prevent tumour formation in mammals. Here we present a clonal approach to address common or dedicated populations of aSCs for homeostasis and growth. Our functional assays on medaka gills demonstrate the existence of separate homeostatic and growth aSCs, which are clonal but differ in their topology. While homeostatic aSCs are fixed, embedded in the tissue, growth aSCs locate at the expanding peripheral zone. Modifications in tissue architecture can convert the homeostatic zone into a growth zone, indicating a leading role for the physical niche defining stem cell output. We hypothesise that physical niches are main players to restrict aScs to a homeostatic function in animals with a fixed adult size.

1903: Prenatal alcohol exposure programs offspring disease: Insulin resistance in adult males in a rat model of acute exposure
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Posted to bioRxiv 27 Jun 2019

Prenatal alcohol exposure programs offspring disease: Insulin resistance in adult males in a rat model of acute exposure
247 downloads developmental biology

Tam M T Nguyen, Sarah E Steane, Karen M Moritz, Lisa K Akison

Alcohol consumption is highly prevalent amongst women of reproductive age. Given that approximately 50% of pregnancies are unplanned, alcohol has the potential to affect fetal development and program chronic disease in offspring. We examined the effect of an acute but moderate prenatal alcohol exposure (PAE) on glucose metabolism, lipid levels and dietary preference in adolescent and/or adult rat offspring. Pregnant Sprague-Dawley rats received an oral gavage of ethanol (1g/kg maternal body weight, n=9 dams) or an equivalent volume of saline (control, n=8 dams) at embryonic days 13.5 and 14.5. PAE resulted in a blood alcohol concentration of 0.05-0.06% 1h post-gavage in dams. Fasting blood glucose concentration was not affected by PAE in offspring at any age, nor were blood glucose levels during a glucose tolerance test (GTT) in 6-month old offspring ( P >0.5). However, there was evidence of insulin resistance in PAE male offspring at 6 months of age, with significantly elevated fasting plasma insulin ( P = 0.001), a tendency for increased first phase insulin secretion during the GTT and impaired glucose clearance following an insulin challenge ( P = 0.007). This was accompanied by modest alterations in protein kinase B (AKT) signalling in adipose tissue. PAE also resulted in reduced calorie consumption by offspring compared to controls ( P = 0.04). These data suggest that a relatively low-level, acute PAE programs metabolic dysfunction in offspring in a sex-specific manner. These results highlight that alcohol consumption during pregnancy has the potential to affect the long-term health of offspring. Key points summary

1904: Drosophila Activin signaling promotes muscle growth through InR/dTORC1 dependent and independent processes
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Posted to bioRxiv 24 Mar 2020

Drosophila Activin signaling promotes muscle growth through InR/dTORC1 dependent and independent processes
247 downloads developmental biology

Myung-Jun Kim, Michael B. O’Connor

The Myostatin/Activin branch of the TGFβ superfamily acts as a negative regulator of mammalian skeletal muscle size, in part, through downregulation of insulin/IGF-1 signaling. Surprisingly, recent studies in Drosophila indicate that Activin signaling acts as a positive regulator of muscle size. Here we demonstrate that Drosophila Activin signaling positively regulates the InR/dTORC1 pathway and the level of MHC, an essential sarcomeric protein, via promoting the transcription of Pdk1 and Akt1. Enhancing InR/dTORC1 signaling in the muscle of Activin pathway mutants restores MHC levels close to wild-type, but only increased the width of muscle cells. In contrast, hyperactivation of the Activin pathway increases the length of muscle cells even when MHC levels were lowered by suppression of dTORC1. Together, these results indicate that Drosophila Activin pathway regulates larval muscle geometry via promoting InR/dTORC1-dependent MHC production and the differential assembly of sarcomeric components into either pre-existing (width) or new (length) sarcomeric units depending on the balance of InR/dTORC1 and Activin signals.

1905: Activin signaling informs the graded pattern of terminal mitosis and hair cell differentiation in the mammalian cochlea
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Posted to bioRxiv 30 Jul 2018

Activin signaling informs the graded pattern of terminal mitosis and hair cell differentiation in the mammalian cochlea
247 downloads developmental biology

Meenakshi Prajapati-DiNubila, Ana Benito-Gonzalez, Erin J Golden, Shuran Zhang, Angelika Doetzlhofer

The mammalian auditory sensory epithelium has one of the most stereotyped cellular patterns known in vertebrates. Mechano-sensory hair cells are arranged in precise rows, with one row of inner and three rows of outer hair cells spanning the length of the spiral-shaped sensory epithelium. Aiding such precise cellular patterning, differentiation of the auditory sensory epithelium is precisely timed and follows a steep longitudinal gradient. The molecular signals that promote auditory sensory differentiation and instruct its graded pattern are largely unknown. Here, we identify Activin A as an activator of hair cell differentiation and show, using mouse genetic approaches, that a local gradient of Activin A signaling within the auditory sensory epithelium times the longitudinal gradient of hair cell differentiation. Furthermore, we provide evidence that Activin-type signaling regulates a radial gradient of terminal mitosis within the auditory sensory epithelium, which constitutes a novel mechanism for limiting the number of inner hair cells being produced.

1906: CBD-1 scaffolds two independent complexes required for eggshell vitelline layer formation and egg activation in C. elegans
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Posted to bioRxiv 14 Jul 2018

CBD-1 scaffolds two independent complexes required for eggshell vitelline layer formation and egg activation in C. elegans
247 downloads developmental biology

Delfina P González, Helen V. Lamb, Diana Partida, Zachary T. Wilson, Marie-Claire Harrison, Julián A. Prieto, James J. Moresco, Jolene K. Diedrich, John R. Yates, Sara K. Olson

Metazoan eggs have a specialized coat of extracellular matrix that aids in sperm-egg recognition. The coat is rapidly remodeled after fertilization to prevent polyspermy and establish a more permanent barrier to protect the developing embryo. In nematodes, this coat is called the vitelline layer, which is remodeled into the outermost layer of a rigid and impermeable eggshell. We have identified three key components of the vitelline layer structural scaffold - PERM-2, PERM-4 and CBD-1, the first such proteins to be described in the nematode C. elegant. CBD-1 recruited PERM-2 and PERM-4 to the nascent vitelline layer via two N- terminal chitin-binding domains. After fertilization, all three proteins redistributed from the zygote surface to the outer eggshell. Depletion of PERM-2 and PERM-4 from the scaffold led to a porous vitelline layer that permitted soluble factors to leak through the eggshell and resulted in embryonic death. In addition to its role in vitelline layer assembly, CBD-1 is also known to scaffold a protein complex required for fertilization and egg activation (EGG-1-5/CHS-1/MBK-2). We found the PERM complex and EGG complex to be structurally and functionally independent, and regulated through distinct domains of CBD-1. CBD-1 is thus a multifaceted regulator that promotes distinct aspects of vitelline layer assembly and egg activation. In sum, our findings identify the first vitelline layer components in nematodes, and provide a foundation through which to explore both conserved and species-specific strategies used by animals to build protective barriers following fertilization.

1907: Gclc deletion in surface-ectoderm tissues induces microphthalmia
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Posted to bioRxiv 13 Jul 2019

Gclc deletion in surface-ectoderm tissues induces microphthalmia
247 downloads developmental biology

Brian Thompson, Ying Chen, Julien Philippe, David Anderson, Jaya Prakash Golla, Emily Davidson, Nicholas Apostolopoulos, Kevin Schey, Nicholas Katsanis, David J Orlicky, David Thompson, Vasilis Vasiliou

Glutamate cysteine ligase catalytic subunit (Gclc) is the catalytic subunit for the glutamate-cysteine ligase (Gcl) enzyme. Gcl catalyzes the rate limiting step in glutathione (GSH) synthesis. Gclc is highly expressed in the developing eye. To define the regulatory role of Gclc in eye development, we developed a novel, Le-Cre transgene-driven, Gclc knockout mouse model. Gclc f/f / Le-Cre Tg/− mice present with deformation of the retina, cornea, iris, and lens, consistent with a microphthalmia phenotype. Controlling for the microphthalmia phenotype of Gclc wt/wt / Le-Cre Tg/− mice revealed that Gclc f/f / Le-Cre Tg/− mice have a more severe microphthalmia phenotype. Thus, the loss of Gclc expression exacerbates the microphthalmia phenotype in Le-Cre mice. Gclc f/f / Le-Cre Tg/− eyes present with reduced retinal and lens epithelium proliferation and increased lens cell death. Imaging mass spectrometry of ocular tissues revealed changes in the intensity and distribution of several lipid species and proteins in the retina and corneas of Gclc f/f / Le-Cre Tg/− eyes. Lastly, using splice-blocking morpholinos and CRISPR/Cas9, we created two gclc knockdown zebrafish models, both of which display a microphthalmia phenotype. Combined, the mouse and zebrafish results indicate that, in chordates, Gclc has a conserved role in regulating eye development. In summary, these novel animal models are useful tools for elucidating the mechanisms involved in microphthalmia development.

1908: Blastula stage specification of avian neural crest
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Posted to bioRxiv 17 Jul 2019

Blastula stage specification of avian neural crest
247 downloads developmental biology

Maneeshi S. Prasad, Eileen Uribe-Querol, Jonathan Marquez, Stephanie Vadasz, Nathan Yardley, Patrick B. Shelar, Rebekah M Charney, Martin I. Garcia-Castro

Cell fate specification defines the earliest steps towards a distinct cell lineage. Neural crest, a multipotent stem cell population, is thought to be specified from the ectoderm, but its varied contributions defy canons of segregation potential and challenges its embryonic origin. Aiming to resolve this conflict, we have assayed the earliest specification of neural crest using blastula stage chick embryos. Specification assays on isolated chick epiblast explants identify an intermediate region specified towards the neural crest cell fate. Furthermore, low density culture suggests that the specification of intermediate cells towards the neural crest lineage is independent of contact mediated induction. Finally, we have validated the regional identity of the intermediate region towards the neural crest cell fate using fate map studies in blastula stage chick embryos. Our results suggest a model of neural crest specification at blastula stage, with restricted ectoderm and mesoderm capacities.

1909: High temperature limits on developmental canalization in the ascidian Ciona intestinalis
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Posted to bioRxiv 06 Dec 2018

High temperature limits on developmental canalization in the ascidian Ciona intestinalis
246 downloads developmental biology

Steven Q. Irvine, Katherine B McNulty, Evelyn M Siler, Rose E Jacobson

The normal embryogenesis of marine animals is typically confined to a species-specific range of temperatures. Within that temperature range development results in a consistent, or canalized, phenotype, whereas above and below the range abnormal phenotypes are produced. This study reveals an abrupt high temperature limit, occurring over a 1-2C range, for normal embryonic development in C. intestinalis. Above that threshold morphological abnormalities in the notochord and other organs are observed, beginning with cleavage and gastrula stages, and becoming more pronounced as embryogenesis proceeds. However, even in highly morphologically abnormal temperature disrupted (TD) embryos, cell type specification, including muscle, endoderm, notochord, and sensory pigment cells is accomplished. An explanation for this finding is that in C. intestinalis cell type specification occurs relatively early in embryogenesis, due to cleavage stage segregation of maternal cytoplasmic determinants and short-range cell interactions, which are largely intact in TD embryos. On the other hand, morphogenesis of the notochord and other structures is dependent on precise cell movement and shape changes after the gastrula stage, which appear to be disrupted above the high temperature threshold. These findings have implications for the relationship between ecology and reproduction in C. intestinalis. More broadly they point to mechanisms behind canalization in animals, such as ascidians, characterized by early, largely autonomous, cell type specification.

1910: Active Notch Signaling is Required for Arm Regeneration in a Brittle Star
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Posted to bioRxiv 13 Dec 2019

Active Notch Signaling is Required for Arm Regeneration in a Brittle Star
246 downloads developmental biology

Vladimir Mashanov, Jennifer Akiona, Maleana Khoury, Jacob Ferrier, Robert Reid, Denis Jacob Machado, Olga Zueva, Daniel Janies

Cell signaling pathways play key roles in coordinating cellular events in development. The Notch signaling pathway is highly conserved across all multicellular animals and is known to coordinate a multitude of diverse cellular events, including proliferation, differentiation, fate specification, and cell death. Specific functions of the pathway are, however, highly context-dependent and are not well characterized in post-traumatic regeneration. Here, we use a small-molecule inhibitor of the pathway (DAPT) to demonstrate that Notch signaling is required for proper arm regeneration in the brittle star Ophioderma brevispin , a highly regenerative member of the phylum Echinodermata. We also employ a transcriptome-wide gene expression analysis (RNA-seq) to characterize the downstream genes controlled by the Notch pathway in the brittle star regeneration. We demonstrate that arm regeneration involves an extensive cross-talk between the Notch pathway and other cell signaling pathways. In the regrowing arm, Notch regulates the composition of the extracellular matrix, cell migration, proliferation, and apoptosis, as well as components of the innate immune response. We also show for the first time that Notch signaling regulates the activity of several transposable elements. Our data also suggests that one of the possible mechanisms through which Notch sustains its activity in the regenerating tissues is via suppression of Neuralized1.

1911: Alternative pathway androgen biosynthesis and human fetal female virilization
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Posted to bioRxiv 15 Apr 2019

Alternative pathway androgen biosynthesis and human fetal female virilization
246 downloads developmental biology

Nicole Reisch, Angela E Taylor, Edson F. Nogueira, Daniel J Asby, Vivek Dhir, Andrew Berry, Nils Krone, Richard J Auchus, Cedric HL Shackleton, Neil A Hanley, Wiebke Arlt

Androgen biosynthesis in the human fetus proceeds through the adrenal sex steroid precursor dehydroepiandrosterone, which is converted towards testosterone in the gonads, followed by further activation to 5α-dihydrotestosterone in genital skin, thereby facilitating male external genital differentiation. Congenital adrenal hyperplasia due to P450 oxidoreductase deficiency results in disrupted dehydroepiandrosterone biosynthesis, explaining undervirilization in affected boys. However, many affected girls are born virilized, despite low circulating androgens. We hypothesized that this is due to a prenatally active, alternative androgen biosynthesis pathway from 17α-hydroxyprogesterone to 5α-dihydrotestosterone, which bypasses dehydroepiandrosterone and testosterone, with increased activity in congenital adrenal hyperplasia variants associated with 17α-hydroxyprogesterone accumulation. Here we employ explant cultures of human fetal organs (adrenal, gonads, genital skin) from the major period of sexual differentiation and show that alternative pathway androgen biosynthesis is active in the fetus, as assessed by liquid chromatography-tandem mass spectrometry. We found androgen receptor expression in male and female genital skin using immunohistochemistry and demonstrated that both 5α-dihydrotestosterone and adrenal explant culture supernatant induce nuclear translocation of the androgen receptor in female genital skin primary cultures. Analyzing urinary steroid excretion by gas chromatography-mass spectrometry, we show that neonates with P450 oxidoreductase deficiency produce androgens through the alternative androgen pathway during the first weeks of life. We provide quantitative in vitro evidence that the corresponding P450 oxidoreductase mutations predominantly support alternative pathway androgen biosynthesis. These results indicate a key role of alternative pathway androgen biosynthesis in the prenatal virilization of girls affected by congenital adrenal hyperplasia due to P450 oxidoreductase deficiency. SIGNIFICANCE In the classic androgen biosynthesis pathway, testosterone is converted to 5α-dihydrotestosterone, a step crucially required for normal male genital virilization. Congenital adrenal hyperplasia (CAH) due to P450 oxidoreductase deficiency (PORD) is an inborn disorder that disrupts classic androgen biosynthesis. However, some affected girls present with severe genital virilization at birth. We hypothesized that this is explained by a prenatally active, alternative biosynthesis pathway to 5α-dihydrotestosterone. We show that adrenals and genital skin cooperate to produce androgens via the alternative pathway during the major period of human sexual differentiation and that neonates with PORD still produce alternative pathway androgens during the first weeks of life. This indicates that alternative pathway androgen biosynthesis drives prenatal virilization in CAH due to PORD.

1912: Dual Role of Jam3b in Early Hematopoietic and Vascular Development
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Posted to bioRxiv 31 May 2019

Dual Role of Jam3b in Early Hematopoietic and Vascular Development
246 downloads developmental biology

Isao Kobayashi, Jingjing Kobayashi-Sun, Yuto Hirakawa, Madoka Ouchi, Koyuki Yasuda, Hiroyasu Kamei, Shigetomo Fukuhara, Masaaki Yamaguchi

In order to efficiently derive hematopoietic stem cells (HSCs) from pluripotent precursors, it is crucial to understand how mesodermal cells acquire hematopoietic or endothelial identity due to their close developmental connection. Although Npas4 has been recently identified as a conserved master regulator of hemato-vascular development, the molecular mechanisms underlying the cell fate divergence between hematopoietic and vascular endothelial cells are still unclear. Here, we show in zebrafish that the divergence of hematopoietic and vascular endothelial cells in mesodermal cells is regulated by Junctional adhesion molecule 3b (Jam3b) via two independent signaling pathways. Mutation of jam3b led to the reduction of npas4l expression in the posterior lateral plate mesoderm and defect of both hematopoietic and vascular development. Mechanistically, we uncover that Jam3b promotes endothelial specification by regulating npas4l expression through the repression of the Rap1a-Erk signaling cascade. Jam3b subsequently promotes hematopoietic development including HSCs by regulating lrrc15 expression in endothelial precursors through the activation of an integrin-dependent signaling cascade. Our data provide insight into the divergent mechanisms for instructing hematopoietic or vascular fates from mesodermal cells.

1913: Loss of zebrafish ctnnd2b results in disorganised forebrain neuron clusters
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Posted to bioRxiv 18 Sep 2018

Loss of zebrafish ctnnd2b results in disorganised forebrain neuron clusters
246 downloads developmental biology

Wolfgang Hofmeister, Raquel Vaz, Steven Edwards, Alfredo Dueñas Rey, Anna Lindstrand

Delta catenin (CTNND2) is an adhesive junction associated protein belonging to the family of p120ct catenins. It is located in the short arm of chromosome 5, a region deleted in Cri-du-chat syndrome. Heterozygous loss of CTNND function has been linked to autism, schizophrenia, and mild intellectual disability with or without dyslexia-like learning difficulties. As to date, most functional studies have focused on homozygous loss of the gene, contradictory to the dominant effect of loss of a single allele observed in neurodevelopmental disorders. Here we show that heterozygous loss of CTNND2 results in a disorganisation and imbalance of neuronal subtypes in forebrain specific regions. Using the zebrafish model, we show that CRISPR/Cas9-induced loss of ctnnd2b but not ctnnd2a results in an increase in isl1-expressing cells and a local reduction of GABA expressing neurons in the optic recess region of the embryonic zebrafish forebrain. Using time-lapse analysis, we found that the disorganised distribution of is1l-expressing forebrain neurons was not due to migration defects, rather an increase in the number if isl1-GFP neurons in the ORR which appear disorganised and show an altered morphology and orientation upon closer analysis. Overall this data suggests that ctnnd2 may affect the differentiation cascade of neuronal subtypes in specific regions of the vertebrate brain.

1914: Ureteric Bud Cells Programmed from Embryonic Stem Cells Obtain Competence for Secondary Induction in the Kidney
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Posted to bioRxiv 01 Aug 2019

Ureteric Bud Cells Programmed from Embryonic Stem Cells Obtain Competence for Secondary Induction in the Kidney
245 downloads developmental biology

Zenglai Tan, Aleksandra Rak-Raszewska, Ilya Skovorodkin, Seppo J. Vainio

Generation of kidney organoids from pluripotent stem cells (PSCs) is regarded as a potentially powerful way to study kidney development, disease, and regeneration. Direct differentiation of PSCs towards renal lineages is well studied, however, most of the studies relates to generation of nephron progenitor population from PSCs. Until now, differentiation of PSCs into ureteric bud (UB) progenitor cells demonstrates limited success. Here, we describe a simple, efficient and reproductive protocol to direct differentiation of mouse embryonic stem cells (mESCs) into UB progenitor cells. The mESC derived UB cells were able to induce nephrogenesis when placed in the interaction with the primary metanephric mesenchyme (pMM). In generated kidney organoids, the embryonic pMM developed nephron structures and the mESC derived UB cells formed network of collecting ducts, connected with the nephron tubules. Altogether, our studies established an uncomplicated and reproducible platform for kidney disease modelling, drug testing and regenerative medicine applications.

1915: Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development.
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Posted to bioRxiv 07 Jan 2019

Glycosylphosphatidylinositol Biosynthesis and Remodeling are Required for Neural Crest Cell, Cardiac and Neural Development.
245 downloads developmental biology

Marshall Lukacs, Tia Roberts, Praneet Chatuverdi, Rolf W. Stottmann

The glycosylphosphatidylinositol (GPI) anchor attaches nearly 150 proteins to the cell surface. Patients with pathogenic variants in GPI biosynthetic pathway genes display an array of phenotypes including seizures, developmental delay, dysmorphic facial features and cleft palate. There is virtually no mechanism to explain these phenotypes. We identified a novel mouse mutant (cleft lip/palate, edema and exencephaly; Clpex) with a hypomorphic mutation in Post-Glycophosphatidylinositol Attachment to Proteins-2 (Pgap2). Pgap2 is one of the final proteins in the GPI biosynthesis pathway and is required for anchor maturation. We found the Clpex mutation results in a global decrease in surface GPI expression. Surprisingly, Pgap2 showed tissue specific expression with enrichment in the affected tissues of the Clpex mutant. We found the phenotype in Clpex mutants is due to apoptosis of neural crest cells (NCCs) and the cranial neuroepithelium, as is observed in the GPI anchored Folate Receptor 1-/- mouse. We showed folinic acid supplementation in utero can rescue the cleft lip phenotype in Clpex. Finally, we generated a novel mouse model of NCC-specific total GPI deficiency in the Wnt1-Cre lineage. These mutants developed median cleft lip and palate demonstrating a cell autonomous role for GPI biosynthesis in NCC development.

1916: Prenatal aromatase inhibition alters postnatal immune function in domestic chickens (Gallus gallus)
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Posted to bioRxiv 17 Jan 2018

Prenatal aromatase inhibition alters postnatal immune function in domestic chickens (Gallus gallus)
245 downloads developmental biology

J.W. Simkins, F. Bonier, Z.M. Benowitz-Fredericks

In birds, exposure to testosterone during embryonic development can suppress immune function; however, it is unclear whether this is caused by direct stimulation of androgen receptors. Estradiol is synthesized from testosterone by the enzyme aromatase, and this conversion is a necessary step in many signaling pathways that are ostensibly testosterone-dependent. Many lines of evidence in mammals indicate that estradiol can affect immune function. We tested the hypothesis that immunosuppressive effects of avian in ovo testosterone exposure are mediated by conversion to estradiol by aromatase, using Fadrozole to inhibit aromatization of endogenous testosterone during a crucial period of embryonic immune system development in domestic chickens (Gallus gallus). We then measured total IgY antibody count, response to PHA challenge, mass of thymus and bursa of Fabricius, and plasma testosterone post-hatch on days 3 and 18. We predicted that if immunomodulation by testosterone is dependent on aromatization, then Fadrozole treatment would lead to elevated immune activity by inhibiting estrogen production. Conversely, if testosterone inhibits immune function directly by binding to androgen receptors, then Fadrozole treatment would likely not alter immune function. Fadrozole treated birds had decreased day 3 plasma IgY antibody titers but there was a strong trend towards increased day 18 thymic mass. Furthermore, Fadrozole treatment generated a positive relationship between testosterone and thymic mass in males, and tended to increase day 18 IgY levels for a given bursal mass in females. There was no effect on PHA response, bursal mass, or plasma testosterone at either age. Overall, Fadrozole treated birds tended to have elevated indicators of immune function, implicating aromatization as a relevant pathway through which developmental exposure to testosterone can affect immunity.

1917: Robust Reconstruction of CRISPR and Tumor Lineage Using Depth Metrics
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Posted to bioRxiv 15 Apr 2019

Robust Reconstruction of CRISPR and Tumor Lineage Using Depth Metrics
245 downloads developmental biology

Ken Sugino, Tzumin Lee

Lineage reconstruction using CRISPR edited barcodes are becoming wide-spread and methods robust against noise are in need. Neighbor-Joining (NJ) algorithm is a robust distance based algorithm extensively used in phylogeny field. NJ is also used for CRISPR-encoded-lineage (CEL) reconstruction with proper re-rooting since NJ is un-rooted algorithm. However, we found NJ works without re-rooting for reconstructing CEL when the lineage contains multiple trees but not for a single tree. Examining why this is the case leads to the idea of depth metrics. The notion of depth metrics also naturally explains why Russell-Rao metric, previously found best metric for CEL reconstruction, works well. Furthermore, based on the probabilistic model of CEL, we constructed a new metric that performs better than Russell-Rao metric. We also propose inferring ancestral code during reconstruction instead of using a linkage method. These, together with Nearest-Neighbor-Interchange resulted in a new robust method for reconstructing CEL or tumor-cell-lineages which share same assumptions as CEL.

1918: The Clathrin adaptor AP-1 and the Rab-stabilizing chaperone Stratum act in two parallel pathways to control the activation of the Notch pathway in Drosophila
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Posted to bioRxiv 21 May 2019

The Clathrin adaptor AP-1 and the Rab-stabilizing chaperone Stratum act in two parallel pathways to control the activation of the Notch pathway in Drosophila
245 downloads developmental biology

Karen Bellec, Isabelle Gicquel, Roland Le Borgne

Drosophila sensory organ precursors divide asymmetrically to generate pIIa/pIIb cells whose identity relies on the differential activation of Notch during cytokinesis. While Notch is present apically and basally relative to the midbody at the pIIa-pIIb interface, only the basal pool of Notch is reported to contribute to Notch activation in the pIIa cell. Such proper intra-lineage signalling therefore requires appropriate apico-basal targeting of Notch, its ligand Delta and its trafficking partner Sanpodo. We previously reported that AP-1 and Stratum regulate the intracellular trafficking of Notch and Sanpodo from the trans-Golgi network to basolateral membrane. Loss of AP-1 or of Stratum caused mild Notch phenotype. Here, we report that the concomitant loss of AP-1 and Stratum result in the stabilization of the apical pool of Notch, Delta and Spdo, the loss of the basal pool of Notch at the pIIa-pIIb interface, and is associated with activation of Notch in the two SOP daughters. We propose that AP-1 and Stratum control two parallel pathways towards plasma membrane and that Notch intra-lineage signalling could also occur at the apical pIIa-pIIb interface.

1919: Protein Phosphatase 1 activity controls a balance between collective and single cell modes of migration
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Posted to bioRxiv 20 Oct 2019

Protein Phosphatase 1 activity controls a balance between collective and single cell modes of migration
245 downloads developmental biology

Yujun Chen, Nirupama Kotian, George Aranjuez, Lin Chen, C. Luke Messer, Ashley Burtscher, Ketki Sawant, Damien Ramel, Xiaobo Wang, Jocelyn A. McDonald

Collective cell migration is central to many developmental and pathological processes. However, the mechanisms that keep cell collectives together and coordinate movement of multiple cells are poorly understood. Using the Drosophila border cell migration model, we find that Protein phosphatase 1 (Pp1) activity controls collective cell cohesion and migration. Inhibition of Pp1 causes border cells to round up, dissociate, and move as single cells with altered motility. We present evidence that Pp1 promotes proper levels of cadherin-catenin complex proteins at cell-cell junctions within the cluster to keep border cells together. Pp1 further restricts actomyosin contractility to the cluster periphery rather than at internal cell-cell contacts. We show that the myosin phosphatase Pp1 complex, which inhibits non-muscle myosin-II (Myo-II) activity, coordinates border cell shape and cluster cohesion. Given the high conservation of Pp1 complexes, this study identifies Pp1 as a major regulator of collective versus single cell migration.

1920: Mediator complex subunit Med19 binds directly GATA DNA-binding zinc finger and functions with Med1 in GATA-driven gene regulation in vivo
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Posted to bioRxiv 04 Apr 2020

Mediator complex subunit Med19 binds directly GATA DNA-binding zinc finger and functions with Med1 in GATA-driven gene regulation in vivo
244 downloads developmental biology

Clément Immarigeon, Sandra Bernat-Fabre, Emmanuelle Guillou, Alexis Verger, Elodie Prince, Mohamed A. Benmedjahed, Adeline Payet, Marie Couralet, Didier Monte, Vincent Villeret, Henri-Marc Bourbon, Muriel Boube

The evolutionarily-conserved multiprotein Mediator complex (MED) serves as an interface between DNA-bound transcription factors (TFs) and the RNA Polymerase II machinery. It has been proposed that each TF interacts with a dedicated MED subunit to induce specific transcriptional responses. However, binary MED subunit - TF partnerships are probably oversimplified models. Using Drosophila TFs of the GATA family - Pannier (Pnr) and Serpent (Srp) - as a model, we have previously established GATA cofactor evolutionarily-conserved function for the Med1 Mediator subunit. Here, we show that another subunit, Med19, is required for GATA-dependent gene expression and interacts physically with Pnr and Srp in cellulo, in vivo and in vitro through their conserved C-zinc finger (ZF), indicating general GATA co-activator functions. Interestingly, Med19 is critical for the regulation of all tested GATA target genes which is not the case for Med1, suggesting differential use of MED subunits by GATAs depending on the target gene. Lastly, despite their presumed distant position within the MED middle module, both subunits interact physically. In conclusion, our data shed new light first on the MED complex, engaging several subunits to mediate TF-driven transcriptional responses and second, on GATA TFs, showing that ZF DNA-binding domain also serves for transactivation.

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