PaperPlayer biorxiv developmental biology

Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.11.245670v1?rss=1

Authors: Tan, S., Huan, P., Liu, B.

Abstract:

The molecular mechanisms of dorsal-ventral (DV) patterning in Spiralia are poorly understood. The few available studies indicate that derived DV patterning mechanisms occurred in particular spiralian lineages and likely were related to the loss of Chordin gene. Here, a functional study of the first spiralian Chordin showed that BMP2/4 and Chordin regulate DV patterning in the mollusk Lottia goshimai, thus revealing the first spiralian case that retains this conserved mechanism. We then showed that Chordin but not BMP2/4 transferred the positional information of the D-quadrant organizer to establish the BMP signaling gradient along the presumed DV axis. Further investigations on the molluscan embryos with influenced DV patterning suggested a role of BMP signaling in regulating the organization of the larval nervous system and indicated that the blastopore localization is correlated with the BMP signaling gradient. These findings provide insights into the evolution of animal DV patterning, the unique development mode of spiralians driven by the D-quadrant organizer, and the evolution of bilaterian body plans.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.249540v1?rss=1

Authors: Haerlingen, B., Opitz, R., Vandernoot, I., Molinaro, A., Shankar, M., Gillotay, P., Trubiroha, A., Costagliola, S.

Abstract:

The thyroid plays an essential role in homeostasis and development, but the extrinsic regulation of its embryonic development remains poorly understood. Recently, we have identified the FGF and BMP pathways to be crucial for thyroid specification and have confirmed the hypothesis that the cardiac mesoderm provides the FGF and BMP ligands to regulate this process. However, it is not clear how these ligands control thyroid specification. To study the molecular mechanisms underlying early thyroid development, we combined a pharmacological approach in zebrafish embryos with genetic models, to modulate the activity of the FGF and BMP pathways at different embryonic stages. We first characterized the expression of the transcription factors pax2a and nkx2.4b - the two main early thyroid markers - in the anterior foregut endoderm and observed that pax2a was expressed from 18 hours post fertilization (hpf) and marked a large endodermal cell population while nkx2.4b was expressed from 24 hpf and marked only a subset of the pax2a-positive endodermal cells. Interestingly, the activity profiles of FGF and BMP coincided with the detection of pax2a and nkx2.4b expression, respectively. Brief modulations of the FGF and/or BMP pathways support the hypothesis that the FGF pathway regulates the expression of pax2a and the BMP pathway regulates the expression of nkx2.4b. Furthermore, inhibition of the BMP pathway during early segmentation has dramatic effects on thyroid specification, probably via the FGF pathway. Together with our previous observations, we propose here, an updated model of early thyroid development in which the foregut endoderm receives several synchronized waves of FGF and BMP signals from the cardiac mesoderm, which result in sequential activation of pax2a and nkx2.4b gene expression and subsequent thyroid specification

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.12.247759v1?rss=1

Authors: Kornberg, T. B., Hatori, R.

Abstract:

Morphogen signaling proteins disperse across tissues to activate signal transduction in target cells. We investigated dispersion of Hedgehog (Hh), Wingless (Wg), and Bone morphogenic protein homolog Decapentaplegic (Dpp) in the Drosophila wing imaginal disc, and found that delivery to targets is regulated. Cells take up <5% Hh produced, and neither amounts taken up nor extent of signaling changes under conditions of Hh production from 50-200% normal amounts. Similarly, cells take up <25% Wg produced, and variation in Wg production from 50-700% normal has no effect on amounts taken up or signaling. Similar properties were observed for Dpp. Wing disc-produced Hh signals to disc-associated tracheal and myoblast as well as an approximately equal number of disc cells, but the extent of signaling in the disc is unaffected by the presence or absence of the tracheal cells and myoblasts. These findings show that target cells do not take up signaling proteins from a common pool and that both the amount and destination of delivered morphogens are regulated.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.249714v1?rss=1

Authors: Andrikou, C., Hejnol, A.

Abstract:

FGF signaling is involved in mesoderm induction in deuterostomes, but not in flies and nematodes, where it has a role in mesoderm patterning and migration. However, comparable studies in other protostomic taxa are missing in order to decipher whether this mesoderm-inducing function of FGF extends beyond the lineage of deuterostomes. Here, we investigated the role of FGF signaling during mesoderm development in three species of lophophorates, a clade within the protostome group Spiralia. Our gene expression analyses show that the molecular patterning of mesoderm development is overall conserved between brachiopods and phoronids, but the spatial and temporal recruitment of transcription factors differs significantly. Moreover, inhibitor experiments demonstrate that FGF signaling is involved in mesoderm formation, morphogenetic movements of gastrulation and posterior axial elongation. Our findings suggest that the inductive role of FGF in mesoderm possibly predates the origin of deuterostomes.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.249961v1?rss=1

Authors: Yue, F., Song, C., Huang, D., Narayanan, N., Qiu, J., Jia, Z., Yuan, Z., Oprescu, S. N., Roseguini, B. T., Deng, M., Kuang, S.

Abstract:

Duchenne Muscular Dystrophy (DMD) is caused by mutation of the muscle membrane protein dystrophin and characterized by severe degeneration of myofibers, progressive muscle wasting and loss of mobility, ultimately cardiorespiratory failure and premature death. Here we report that skeletal muscle-specific knockout (KO) of Phosphatase and tensin homolog (Pten) gene in an animal model of DMD (mdx mice) alleviates myofiber degeneration and restores muscle function without increasing tumor incidences. Specifically, Pten KO normalizes myofiber size and prevents muscular atrophy, and improves grip strength and exercise performance of mdx mice. Pten KO also reduces fibrosis and inflammation; and ameliorates muscle pathology in mdx mice. Moreover, we found that Pten KO upregulates extracellular matrix and basement membrane components positively correlated to wound healing, but suppresses negative regulators of wound healing and lipid biosynthesis; and restores the integrity of muscle basement membrane in mdx mice. Importantly, pharmacological inhibition of PTEN similarly ameliorates muscle pathology and improves muscle integrity and function in mdx mice. Our finding provides evidence that PTEN inhibition may represent a potential therapeutic strategy to restore muscle function in DMD.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.13.247569v1?rss=1

Authors: Ziegler, B., Yiallouros, I., Trageser, B., Kumar, S., Mercker, M., Kling, S., Fath, M., Warnken, U., Schnoelzer, M., Holstein, T. W., Hartl, M., Marciniak-Czochra, A., Stetefeld, J., Stoecker, W., Oezbek, S.

Abstract:

The Hydra head organizer acts as a signaling center that initiates and maintains the primary body axis in steady state polyps and during budding or regeneration. Wnt/beta-Catenin signaling functions as a primary cue controlling this process, but how Wnt ligand activity is locally restricted at the protein level is poorly understood. Here we report the identification of an astacin family proteinase as a Wnt processing factor. Hydra astacin-7 (HAS-7) is expressed from gland cells as an apical-distal gradient in the body column, peaking close beneath the tentacle zone. HAS-7 siRNA knockdown abrogates HyWnt3 proteolysis in the head tissue and induces a robust double axis phenotype, which is rescued by simultaneous HyWnt3 knockdown. Accordingly, double axes are also observed in conditions of increased Wnt levels as in transgenic actin::HyWnt3 and HyDkk1/2/4 siRNA treated animals. HyWnt3-induced double axes in Xenopus embryos could be rescued by co-injection of HAS-7 mRNA. Mathematical modelling combined with experimental promotor analysis indicate an indirect regulation of HAS-7 by beta-Catenin, expanding the classical Turing-type activator-inhibitor model. Our data suggest a negative regulatory function of Wnt processing astacin proteinases in the global patterning of the oral-aboral axis in Hydra.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.12.247585v1?rss=1

Authors: Boettcher, A., Buettner, M., Tritschler, S., Sterr, M., Aliluev, A., Oppenlaender, L., Burtscher, I., Sass, S., Irmler, M., Beckers, J., Ziegenhain, C., Enard, W., Schamberger, A. C., Verhamme, F. M., Eickelberg, O., Theis, F. J., Lickert, H.

Abstract:

A detailed understanding of intestinal stem cell (ISC) self-renewal and differentiation is required to better treat chronic intestinal diseases. However, different models of ISC lineage hierarchy and segregation are debated. Here we report the identification of Lgr5+ ISCs that express Flattop (Fltp), a Wnt/planar cell polarity (PCP) reporter and effector gene. Lineage labelling revealed that Wnt/PCP-activated Fltp+ ISCs are primed either towards the enteroendocrine or the Paneth cell lineage in vivo. Integration of time-resolved lineage labelling with genome-wide and targeted single-cell gene expression analysis allowed us to delineate the ISC differentiation path into enteroendocrine and Paneth cells at the molecular level. Strikingly, we found that both lineages are directly recruited from ISCs via unipotent transition states, challenging the existence of formerly predicted bi- or multipotent secretory progenitors. Transitory cells that mature into Paneth cells are quiescent and express both stem cell and secretory lineage genes, indicating that these cells are the previously described Lgr5+ label-retaining cells. Wnt/PCP-activated Lgr5+ ISCs are indistinguishable from Wnt/beta catenin-activated Lgr5+ ISCs based on the expression of stem-cell signature or secretory lineage-specifying genes but possess less self-renewal activity. This suggests that lineage priming and cell-cycle exit is triggered at the post-transcriptional level by polarity cues and a switch from canonical to non-canonical Wnt/PCP signalling. Taken together, we identified the Wnt/PCP pathway as a new niche signal and polarity cue regulating stem cell fate. Active Wnt/PCP signalling represents one of the earliest events in ISC lineage priming towards the Paneth and enteroendocrine cell fate, preceding lateral inhibition and expression of secretory lineage-specifying genes. Thus, our findings provide a better understanding of the niche signals and redefine the mechanisms underlying ISC lineage hierarchy and segregation.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.12.248716v1?rss=1

Authors: GRAY, R., Gonzalez, R., Ackerman, S. D., Minowa, R. C., Griest, J. F., Bayrak, M. N., Troutwine, B. R., Canter, S., Monk, K. R., Sepich, D. S., Solnica-Krezel, L.

Abstract:

The spinal vertebral column gives structural support for the adult body plan, protects the spinal cord, and provides muscle attachment and stability, which allows the animal to move within its environment. The development and maturation of the spine and its physiology involve the integration of multiple musculoskeletal tissues including bone, cartilage, and fibrocartilaginous joints, as well as innervation and control by the nervous system. One of the most common disorders of the spine in human is adolescent idiopathic scoliosis (AIS), which is characterized by the onset of an abnormal lateral curvature of the spine of <10{degrees} around adolescence, in otherwise healthy children. The genetic basis of AIS is largely unknown. Systematic genome-wide mutagenesis screens for embryonic phenotypes in zebrafish have been instrumental in the understanding of early patterning of embryonic tissues necessary to build and pattern the embryonic spine. However, the mechanisms required for postembryonic maturation and homeostasis of the spine remain poorly understood. Here we report the results from a small-scale forward genetic screen for adult-viable recessive and dominant mutant zebrafish, displaying overt morphological abnormalities of the adult spine. Germline mutations induced with N-ethyl N-nitrosourea (ENU) were transmitted and screened for dominant phenotypes in 1,229 F1 animals, and subsequently bred to homozygosity in F3 families, from these, 314 haploid genomes were screened for recessive phenotypes. We cumulatively found 39 adult-viable (3 dominant and 36 recessive) mutations each leading to a defect in the morphogenesis of the spine. The largest phenotypic group displayed larval onset axial curvatures, leading to whole-body scoliosis without vertebral dysplasia in adult fish. Pairwise complementation testing within this phenotypic group revealed at least 16 independent mutant loci. Using massively-parallel whole genome or whole exome sequencing and meiotic mapping we defined the molecular identity of several loci for larval onset whole-body scoliosis in zebrafish. We identified a new mutation in the skolios/kinesin family member 6 (kif6) gene, causing neurodevelopmental and ependymal cilia defects in mouse and zebrafish. We also report several recessive alleles of the scospondin and a disintegrin and metalloproteinase with thrombospondin motifs 9 (adamts9) genes, which all display defects in spine morphogenesis. Many of the alleles characterized thus far are non-synonymous mutations in known essential scospondin and adamts9 genes. Our results provide evidence of monogenic traits that are critical for normal spine development in zebrafish, that may help to establish new candidate risk loci for spine disorders in humans.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.12.246512v1?rss=1

Authors: Chavkin, N. W., Genet, G., Poulet, M., Genet, N., Marziano, C., Vasavada, H., Nelson, E. A., Kour, A., McDonnell, S. P., Huba, M., Walsh, K., Hirschi, K. K.

Abstract:

Formation and maturation of a functional blood vascular system is required for the development and maintenance of all tissues in the body. During the process of blood vessel development, primordial endothelial cells are formed and become specified toward arterial or venous fates to generate a circulatory network that provides nutrients and oxygen to, and removes metabolic waste from, all tissues1-3. Specification of arterial and venous endothelial cells occurs in conjunction with suppression of endothelial cell cycle progression4,5, and endothelial cell hyperproliferation is associated with potentially lethal arterial-venous malformations6. However, the mechanistic role that cell cycle state plays in arterial-venous specification is unknown. Herein, studying retinal vascular development in Fucci2aR reporter mice7, we found that venous and arterial endothelial cells are in distinct cell cycle states during development and in adulthood. That is, venous endothelial cells reside in early G1 state, while arterial endothelial cells reside in late G1 state. Endothelial cells in early vs. late G1 exhibited significant differences in gene expression and activity, especially among BMP/TGF-B; signaling components. The early G1 state was found to be essential for BMP4-induced venous specification, whereas late G1 state is essential for TGF-B1-induced arterial specification. In a mouse model of endothelial cell hyperproliferation and disrupted vascular remodeling, pharmacological inhibition of endothelial cell cycle rescues the arterial-venous specification defects. Collectively, our results show that endothelial cell cycle control plays a key role in arterial-venous network formation, and distinct cell cycle states provide distinct windows of opportunity for the molecular induction of arterial vs. venous specification.

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Link to bioRxiv paper:

http://biorxiv.org/cgi/content/short/2020.08.10.244590v1?rss=1

Authors: Ganassi, M., Badodi, S., Wanders, K., Zammit, P. S., Hughes, S. M.

Abstract:

Growth and maintenance of skeletal muscle fibres depend on coordinated activation and return to quiescence of resident muscle stem-cells (MuSCs). The transcription factor Myogenin (Myog) regulates myocyte fusion during development, but its role in adult myogenesis remains unclear. In contrast to mice, myog-/- zebrafish are viable, but have hypotrophic muscles. By isolating adult myofibres with associated MuSCs we found that myog-/- myofibres have severely reduced nuclear number, but increased myonuclear domain size. Expression of fusogenic genes is decreased, pax7 upregulated, MuSCs are fivefold more numerous and mis-positioned throughout the length of myog-/- myofibers instead of localising at myofibre ends as in wild-type. Loss of Myog dysregulates mTORC1 signalling, resulting in an 'alerted' state of MuSCs, which display precocious activation and faster cell cycle entry ex vivo, concomitant with myod upregulation. Thus, beyond controlling myocyte fusion, Myog influences the MuSC:niche relationship, demonstrating a multi-level contribution to muscle homeostasis throughout life.

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