Pub Date : 2020-08-10DOI: 10.1101/2020.08.09.242933
Majed Layous, Lama Khalaily, Tsvia Gildor, Smadar Ben-Tabou de-Leon
Deoxygenation, the reduction of oxygen level in the oceans induced by global warming and anthropogenic disturbances, is a major threat to marine life. Acute diurnal changes in oxygen levels could be especially harmful to vertebrate and sea urchin embryos that utilize endogenous hypoxia gradients to drive morphogenetic events during normal development. Here we show that the tolerance to hypoxic conditions changes between different developmental stages of the sea urchin embryo, due to the structure of the gene regulatory networks (GRNs). We demonstrate that during normal development, bone morphogenetic protein (BMP) pathway restricts the activity of the vascular endothelial growth factor (VEGF) pathway to two lateral domains and by that controls proper skeletal patterning. Hypoxia applied during early development strongly perturbs the activity of Nodal and BMP pathways that affect VEGF pathway, dorsal-ventral (DV) and skeletogenic patterning. These pathways are largely unaffected by hypoxia applied after DV axis formation. We propose that the structure of the DV GRN, that includes feedback and feedforward loops, increases its resilience to changes of the initial oxygen gradients and helps the embryos tolerate transient hypoxia.
{"title":"The tolerance to hypoxia is defined by a time-sensitive response of the gene regulatory network in sea urchin embryos","authors":"Majed Layous, Lama Khalaily, Tsvia Gildor, Smadar Ben-Tabou de-Leon","doi":"10.1101/2020.08.09.242933","DOIUrl":"https://doi.org/10.1101/2020.08.09.242933","url":null,"abstract":"Deoxygenation, the reduction of oxygen level in the oceans induced by global warming and anthropogenic disturbances, is a major threat to marine life. Acute diurnal changes in oxygen levels could be especially harmful to vertebrate and sea urchin embryos that utilize endogenous hypoxia gradients to drive morphogenetic events during normal development. Here we show that the tolerance to hypoxic conditions changes between different developmental stages of the sea urchin embryo, due to the structure of the gene regulatory networks (GRNs). We demonstrate that during normal development, bone morphogenetic protein (BMP) pathway restricts the activity of the vascular endothelial growth factor (VEGF) pathway to two lateral domains and by that controls proper skeletal patterning. Hypoxia applied during early development strongly perturbs the activity of Nodal and BMP pathways that affect VEGF pathway, dorsal-ventral (DV) and skeletogenic patterning. These pathways are largely unaffected by hypoxia applied after DV axis formation. We propose that the structure of the DV GRN, that includes feedback and feedforward loops, increases its resilience to changes of the initial oxygen gradients and helps the embryos tolerate transient hypoxia.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"23 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"80831182","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-07-24DOI: 10.1101/2020.07.24.219394
M. Ichinose, Nobumi Suzuki, Tongtong Wang, Hiroki Kobayashi, L. Vrbanac, Jia Q. Ng, Josephine A. Wright, T. Lannagan, Krystyna A. Gieniec, Martin Lewis, Ryota Ando, A. Enomoto, S. Koblar, P. Thomas, D. Worthley, S. Woods
Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here we show that expression of the BMP antagonist, Grem1, marks a neuroprogenitor that gives rise to layer V and VI glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA seq analysis of differentially expressed transcripts between FACS sorted Grem1 positive and negative cells was performed. We also generated Emx1-cre mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers V and VI and impaired motor balance and fear sensitivity compared to littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex. Summary statement The BMP antagonist, Grem1, marks neuroprogenitors that give rise to deep layer glutamatergic neurons in the embryonic mouse brain. Grem1 conditional knockout mice display cortical and behavioural abnormalities.
{"title":"The BMP antagonist gremlin 1 contributes to the development of cortical excitatory neurons, motor balance and fear responses","authors":"M. Ichinose, Nobumi Suzuki, Tongtong Wang, Hiroki Kobayashi, L. Vrbanac, Jia Q. Ng, Josephine A. Wright, T. Lannagan, Krystyna A. Gieniec, Martin Lewis, Ryota Ando, A. Enomoto, S. Koblar, P. Thomas, D. Worthley, S. Woods","doi":"10.1101/2020.07.24.219394","DOIUrl":"https://doi.org/10.1101/2020.07.24.219394","url":null,"abstract":"Bone morphogenetic protein (BMP) signaling is required for early forebrain development and cortical formation. How the endogenous modulators of BMP signaling regulate the structural and functional maturation of the developing brain remains unclear. Here we show that expression of the BMP antagonist, Grem1, marks a neuroprogenitor that gives rise to layer V and VI glutamatergic neurons in the embryonic mouse brain. Lineage tracing of Grem1-expressing cells in the embryonic brain was examined by administration of tamoxifen to pregnant Grem1creERT Rosa26LSLTdtomato mice at 13.5 days post coitum (dpc), followed by collection of embryos later in gestation. In addition, at 14.5 dpc, bulk mRNA seq analysis of differentially expressed transcripts between FACS sorted Grem1 positive and negative cells was performed. We also generated Emx1-cre mediated Grem1 conditional knockout mice (Emx1-Cre;Grem1flox/flox) in which the Grem1 gene was deleted specifically in the dorsal telencephalon. Grem1Emx1cKO animals had reduced cortical thickness, especially layers V and VI and impaired motor balance and fear sensitivity compared to littermate controls. This study has revealed new roles for Grem1 in the structural and functional maturation of the developing cortex. Summary statement The BMP antagonist, Grem1, marks neuroprogenitors that give rise to deep layer glutamatergic neurons in the embryonic mouse brain. Grem1 conditional knockout mice display cortical and behavioural abnormalities.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"77694911","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-07-08DOI: 10.1101/2020.07.08.193813
Toby G R Andrews, Wolfram Pönisch, E. Paluch, B. Steventon, Èlia Benito-Gutiérrez
During development, embryonic tissues are formed by the dynamic behaviours of their constituent cells, whose collective actions are tightly regulated in space and time. To understand such cell behaviours and how they have evolved, it is necessary to develop quantitative approaches to map out morphogenesis, so comparisons can be made across different tissues and organisms. With this idea in mind, here we sought to investigate ancestral principles of notochord development, by building a quantitative portrait of notochord morphogenesis in the amphioxus embryo – a basally-branching member of the chordate phylum. To this end, we developed a single-cell morphometrics pipeline to comprehensively catalogue the morphologies of thousands of notochord cells, and to project them simultaneously into a common mathematical space termed morphospace. This approach revealed complex patterns of cell-type specific shape trajectories, akin to those obtained using single-cell genomic approaches. By spatially mapping single-cell shape trajectories in whole segmented notochords, we found evidence of spatial and temporal variation in developmental dynamics. Such variations included temporal gradients of morphogenesis spread across the anterior-posterior axis, divergence of trajectories to different morphologies, and the convergence of different trajectories onto common morphologies. Through geometric modelling, we also identified an antagonistic relationship between cell shape regulation and growth that enables convergent extension to occur in two steps. First, by allowing growth to counterbalance loss of anterior-posterior cell length during cell intercalation. Secondly, by allowing growth to further increase cell length once cells have intercalated and aligned to the axial midline, thereby facilitating a second phase of tissue elongation. Finally, we show that apart from a complex coordination of individual cellular behaviours, posterior addition from proliferating progenitors is essential for full notochord elongation in amphioxus, a mechanism previously described only in vertebrates. This novel approach to quantifying morphogenesis paves the way towards comparative studies, and mechanistic explanations for the emergence of form over developmental and evolutionary time scales.
{"title":"Single-cell morphometrics reveals ancestral principles of notochord development","authors":"Toby G R Andrews, Wolfram Pönisch, E. Paluch, B. Steventon, Èlia Benito-Gutiérrez","doi":"10.1101/2020.07.08.193813","DOIUrl":"https://doi.org/10.1101/2020.07.08.193813","url":null,"abstract":"During development, embryonic tissues are formed by the dynamic behaviours of their constituent cells, whose collective actions are tightly regulated in space and time. To understand such cell behaviours and how they have evolved, it is necessary to develop quantitative approaches to map out morphogenesis, so comparisons can be made across different tissues and organisms. With this idea in mind, here we sought to investigate ancestral principles of notochord development, by building a quantitative portrait of notochord morphogenesis in the amphioxus embryo – a basally-branching member of the chordate phylum. To this end, we developed a single-cell morphometrics pipeline to comprehensively catalogue the morphologies of thousands of notochord cells, and to project them simultaneously into a common mathematical space termed morphospace. This approach revealed complex patterns of cell-type specific shape trajectories, akin to those obtained using single-cell genomic approaches. By spatially mapping single-cell shape trajectories in whole segmented notochords, we found evidence of spatial and temporal variation in developmental dynamics. Such variations included temporal gradients of morphogenesis spread across the anterior-posterior axis, divergence of trajectories to different morphologies, and the convergence of different trajectories onto common morphologies. Through geometric modelling, we also identified an antagonistic relationship between cell shape regulation and growth that enables convergent extension to occur in two steps. First, by allowing growth to counterbalance loss of anterior-posterior cell length during cell intercalation. Secondly, by allowing growth to further increase cell length once cells have intercalated and aligned to the axial midline, thereby facilitating a second phase of tissue elongation. Finally, we show that apart from a complex coordination of individual cellular behaviours, posterior addition from proliferating progenitors is essential for full notochord elongation in amphioxus, a mechanism previously described only in vertebrates. This novel approach to quantifying morphogenesis paves the way towards comparative studies, and mechanistic explanations for the emergence of form over developmental and evolutionary time scales.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87634706","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-06-30DOI: 10.1101/2020.06.29.179291
Sophie Colombo, V. Petit, Roselyne Y Wagner, D. Champeval, I. Yajima, F. Gesbert, I. Davidson, V. Delmas, L. Larue
The canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates Mitf-M transcription, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, while a small number of second wave melanocytes is derived from Schwann-cell precursors (SCPs). We investigated the influence of β-catenin in the development of melanocytes of the first and second waves by generating mice expressing a constitutively active form of β-catenin in cells expressing tyrosinase. Constitutive activation of β-catenin did not affect the development of truncal melanoblasts, but led to a marked hyperpigmentation of the paws. By activating β-catenin at various stages of development (E8.5-E11.5), we showed that the activation of β-catenin in bipotent SCPs favored melanoblast specification at the expense of Schwann cells in the limbs within a specific temporal window. In addition, hyperactivation of the Wnt/β-catenin pathway repressed FoxD3 expression, which is necessary for Schwann cell development, through Mitf-M activation. In conclusion, β-catenin overexpression promotes SCP cell-fate decisions towards the melanocyte lineage. Summary statement Activation of β-catenin in bipotent Schwann-cell precursors during a specific developmental window, induces MITF and represses FoxD3 to promote melanoblast cell fate at the expense of Schwann cells in limbs.
{"title":"Stabilization of β-catenin promotes melanocyte specification at the expense of the Schwann cell lineage","authors":"Sophie Colombo, V. Petit, Roselyne Y Wagner, D. Champeval, I. Yajima, F. Gesbert, I. Davidson, V. Delmas, L. Larue","doi":"10.1101/2020.06.29.179291","DOIUrl":"https://doi.org/10.1101/2020.06.29.179291","url":null,"abstract":"The canonical Wnt/β-catenin pathway governs a multitude of developmental processes in various cell lineages, including the melanocyte lineage. Indeed, β-catenin regulates Mitf-M transcription, the master regulator of this lineage. The first wave of melanocytes to colonize the skin is directly derived from neural crest cells, while a small number of second wave melanocytes is derived from Schwann-cell precursors (SCPs). We investigated the influence of β-catenin in the development of melanocytes of the first and second waves by generating mice expressing a constitutively active form of β-catenin in cells expressing tyrosinase. Constitutive activation of β-catenin did not affect the development of truncal melanoblasts, but led to a marked hyperpigmentation of the paws. By activating β-catenin at various stages of development (E8.5-E11.5), we showed that the activation of β-catenin in bipotent SCPs favored melanoblast specification at the expense of Schwann cells in the limbs within a specific temporal window. In addition, hyperactivation of the Wnt/β-catenin pathway repressed FoxD3 expression, which is necessary for Schwann cell development, through Mitf-M activation. In conclusion, β-catenin overexpression promotes SCP cell-fate decisions towards the melanocyte lineage. Summary statement Activation of β-catenin in bipotent Schwann-cell precursors during a specific developmental window, induces MITF and represses FoxD3 to promote melanoblast cell fate at the expense of Schwann cells in limbs.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-06-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"81445677","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-06-02DOI: 10.1101/2020.06.01.127654
Can Aztekin, T. Hiscock, J. Gurdon, J. Jullien, J. Marioni, B. Simons
Absence of a specialised wound epidermis is hypothesised to block limb regeneration in higher vertebrates. To elucidate the cellular and molecular determinants of this tissue, we performed single-cell transcriptomics in regeneration-competent, -restricted, and -incompetent Xenopus tadpoles. We identified apical-ectodermal-ridge (AER) cells as the specialised wound epidermis, and found that their abundance on the amputation plane correlates with regeneration potential and injury-induced mesenchymal plasticity. By using ex vivo regenerating limb cultures, we demonstrate that extrinsic cues produced during limb development block AER cell formation. We identify Noggin, a morphogen expressed in cartilage/bone progenitor cells, as one of the key inhibitors of AER cell formation in regeneration-incompetent tadpoles. Extrinsic inhibitory cues can be overridden by Fgf10, which operates upstream of Noggin and blocks chondrogenesis. Together, these results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates. One Sentence Summary Extrinsic cues associated with chondrogenic progression inhibit AER cell formation and restrict limb regeneration potential.
{"title":"Secreted inhibitors drive the loss of regeneration competence in Xenopus limbs","authors":"Can Aztekin, T. Hiscock, J. Gurdon, J. Jullien, J. Marioni, B. Simons","doi":"10.1101/2020.06.01.127654","DOIUrl":"https://doi.org/10.1101/2020.06.01.127654","url":null,"abstract":"Absence of a specialised wound epidermis is hypothesised to block limb regeneration in higher vertebrates. To elucidate the cellular and molecular determinants of this tissue, we performed single-cell transcriptomics in regeneration-competent, -restricted, and -incompetent Xenopus tadpoles. We identified apical-ectodermal-ridge (AER) cells as the specialised wound epidermis, and found that their abundance on the amputation plane correlates with regeneration potential and injury-induced mesenchymal plasticity. By using ex vivo regenerating limb cultures, we demonstrate that extrinsic cues produced during limb development block AER cell formation. We identify Noggin, a morphogen expressed in cartilage/bone progenitor cells, as one of the key inhibitors of AER cell formation in regeneration-incompetent tadpoles. Extrinsic inhibitory cues can be overridden by Fgf10, which operates upstream of Noggin and blocks chondrogenesis. Together, these results indicate that manipulation of the extracellular environment and/or chondrogenesis may provide a strategy to restore regeneration potential in higher vertebrates. One Sentence Summary Extrinsic cues associated with chondrogenic progression inhibit AER cell formation and restrict limb regeneration potential.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"9 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"86568896","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-04-07DOI: 10.1101/2020.04.06.027599
M. Vigano, Clara-Maria Ell, Manuela M M Kustermann, Gustavo Aguilar, S. Matsuda, Ning Zhao, T. Stasevich, George Pyrowolakis, M. Affolter
ABSTRACT Cellular development and function rely on highly dynamic molecular interactions among proteins distributed in all cell compartments. Analysis of these interactions has been one of the main topics in cellular and developmental research, and has been mostly achieved by the manipulation of proteins of interest (POIs) at the genetic level. Although genetic strategies have significantly contributed to our current understanding, targeting specific interactions of POIs in a time- and space-controlled manner or analysing the role of POIs in dynamic cellular processes, such as cell migration or cell division, would benefit from more-direct approaches. The recent development of specific protein binders, which can be expressed and function intracellularly, along with advancement in synthetic biology, have contributed to the creation of a new toolbox for direct protein manipulations. Here, we have selected a number of short-tag epitopes for which protein binders from different scaffolds have been generated and showed that single copies of these tags allowed efficient POI binding and manipulation in living cells. Using Drosophila, we also find that single short tags can be used for POI manipulation in vivo. Summary: Single copies of short epitope tags were inserted into proteins of interest, allowing for in vivo binding and manipulation of the resulting chimeric proteins by genetically encoded epitope binders.
{"title":"Protein manipulation using single copies of short peptide tags in cultured cells and in Drosophila melanogaster","authors":"M. Vigano, Clara-Maria Ell, Manuela M M Kustermann, Gustavo Aguilar, S. Matsuda, Ning Zhao, T. Stasevich, George Pyrowolakis, M. Affolter","doi":"10.1101/2020.04.06.027599","DOIUrl":"https://doi.org/10.1101/2020.04.06.027599","url":null,"abstract":"ABSTRACT Cellular development and function rely on highly dynamic molecular interactions among proteins distributed in all cell compartments. Analysis of these interactions has been one of the main topics in cellular and developmental research, and has been mostly achieved by the manipulation of proteins of interest (POIs) at the genetic level. Although genetic strategies have significantly contributed to our current understanding, targeting specific interactions of POIs in a time- and space-controlled manner or analysing the role of POIs in dynamic cellular processes, such as cell migration or cell division, would benefit from more-direct approaches. The recent development of specific protein binders, which can be expressed and function intracellularly, along with advancement in synthetic biology, have contributed to the creation of a new toolbox for direct protein manipulations. Here, we have selected a number of short-tag epitopes for which protein binders from different scaffolds have been generated and showed that single copies of these tags allowed efficient POI binding and manipulation in living cells. Using Drosophila, we also find that single short tags can be used for POI manipulation in vivo. Summary: Single copies of short epitope tags were inserted into proteins of interest, allowing for in vivo binding and manipulation of the resulting chimeric proteins by genetically encoded epitope binders.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"48 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-04-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90829316","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-03-10DOI: 10.1101/2020.06.30.179952
T. Cahill, Xin Sun, Christophe Ravaud, Cristina Villa del Campo, K. Klaourakis, Irina-Elena Lupu, Allegra M. Lord, Cathy Browne, S. Jacobsen, D. Greaves, D. Jackson, S. Cowley, W. James, R. Choudhury, J. Vieira, P. Riley
ABSTRACT Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the subepicardial compartment of the developing heart coincides with the emergence of new lymphatics, and that macrophages interact closely with the nascent lymphatic capillaries. Consequently, global macrophage deficiency led to extensive vessel disruption, with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and foetal liver. Moreover, the Cx3cr1+ myeloid lineage was found to play essential functions in the remodelling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature. Highlighted Article: Tissue-resident macrophages are indispensable mediators of lymphatic vessel formation during heart development, and function to remodel the vascular plexus.
{"title":"Tissue-resident macrophages regulate lymphatic vessel growth and patterning in the developing heart","authors":"T. Cahill, Xin Sun, Christophe Ravaud, Cristina Villa del Campo, K. Klaourakis, Irina-Elena Lupu, Allegra M. Lord, Cathy Browne, S. Jacobsen, D. Greaves, D. Jackson, S. Cowley, W. James, R. Choudhury, J. Vieira, P. Riley","doi":"10.1101/2020.06.30.179952","DOIUrl":"https://doi.org/10.1101/2020.06.30.179952","url":null,"abstract":"ABSTRACT Macrophages are components of the innate immune system with key roles in tissue inflammation and repair. It is now evident that macrophages also support organogenesis, but few studies have characterized their identity, ontogeny and function during heart development. Here, we show that the distribution and prevalence of resident macrophages in the subepicardial compartment of the developing heart coincides with the emergence of new lymphatics, and that macrophages interact closely with the nascent lymphatic capillaries. Consequently, global macrophage deficiency led to extensive vessel disruption, with mutant hearts exhibiting shortened and mis-patterned lymphatics. The origin of cardiac macrophages was linked to the yolk sac and foetal liver. Moreover, the Cx3cr1+ myeloid lineage was found to play essential functions in the remodelling of the lymphatic endothelium. Mechanistically, macrophage hyaluronan was required for lymphatic sprouting by mediating direct macrophage-lymphatic endothelial cell interactions. Together, these findings reveal insight into the role of macrophages as indispensable mediators of lymphatic growth during the development of the mammalian cardiac vasculature. Highlighted Article: Tissue-resident macrophages are indispensable mediators of lymphatic vessel formation during heart development, and function to remodel the vascular plexus.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73937805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-02-15DOI: 10.1101/2020.02.14.949701
Dhruv Raina, Azra Bahadori, A. Stanoev, Michelle Protzek, A. Koseska, C. Schröter
During embryonic development and tissue homeostasis, reproducible proportions of differentiated cell types are specified from populations of multipotent precursor cells. Molecular mechanisms that enable both robust cell type proportioning despite variable initial conditions in the precursor cells, as well as the re-establishment of these proportions upon perturbations in a developing tissue remain to be characterized. Here we report that the differentiation of robust proportions of epiblast-like and primitive endoderm-like cells in mouse embryonic stem cell cultures emerges at the population level through cell-cell communication via a short-range FGF4 signal. We characterize the molecular and dynamical properties of the communication mechanism, and show how it controls both robust cell type proportioning from a wide range of experimentally controlled initial conditions, as well as the autonomous re-establishment of these proportions following the isolation of one cell type. The generation and maintenance of reproducible proportions of discrete cell types is a new function for FGF signaling that may operate in a range of developing tissues.
{"title":"Cell-cell communication through FGF4 generates and maintains robust proportions of differentiated cell types in embryonic stem cells","authors":"Dhruv Raina, Azra Bahadori, A. Stanoev, Michelle Protzek, A. Koseska, C. Schröter","doi":"10.1101/2020.02.14.949701","DOIUrl":"https://doi.org/10.1101/2020.02.14.949701","url":null,"abstract":"During embryonic development and tissue homeostasis, reproducible proportions of differentiated cell types are specified from populations of multipotent precursor cells. Molecular mechanisms that enable both robust cell type proportioning despite variable initial conditions in the precursor cells, as well as the re-establishment of these proportions upon perturbations in a developing tissue remain to be characterized. Here we report that the differentiation of robust proportions of epiblast-like and primitive endoderm-like cells in mouse embryonic stem cell cultures emerges at the population level through cell-cell communication via a short-range FGF4 signal. We characterize the molecular and dynamical properties of the communication mechanism, and show how it controls both robust cell type proportioning from a wide range of experimentally controlled initial conditions, as well as the autonomous re-establishment of these proportions following the isolation of one cell type. The generation and maintenance of reproducible proportions of discrete cell types is a new function for FGF signaling that may operate in a range of developing tissues.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"18 1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"91214635","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-01DOI: 10.1101/2020.05.07.083493
Aihua Mao, Mingming Zhang, Linwei Li, Jie Liu, Guozhu Ning, Yu Cao, Qiang Wang
ABSTRACT The paired pharyngeal arch arteries (PAAs) are transient blood vessels connecting the heart with the dorsal aorta during embryogenesis. Although PAA malformations often occur along with pharyngeal pouch defects, the functional interaction between these adjacent tissues remains largely unclear. Here, we report that pharyngeal pouches are essential for PAA progenitor specification in zebrafish embryos. We reveal that the segmentation of pharyngeal pouches coincides spatiotemporally with the emergence of PAA progenitor clusters. These pouches physically associate with pharyngeal mesoderm in discrete regions and provide a niche microenvironment for PAA progenitor commitment by expressing BMP proteins. Specifically, pouch-derived BMP2a and BMP5 are the primary niche cues responsible for activating the BMP/Smad pathway in pharyngeal mesoderm, thereby promoting progenitor specification. In addition, BMP2a and BMP5 play an inductive function in the expression of the cloche gene npas4l in PAA progenitors. cloche mutants exhibit a striking failure to specify PAA progenitors and display ectopic expression of head muscle markers in the pharyngeal mesoderm. Therefore, our results support a crucial role for pharyngeal pouches in establishing a progenitor niche for PAA morphogenesis via BMP2a/5 expression. Summary: Pharyngeal pouch-derived BMP2a and BMP5 are the key niche cues that induce arch artery progenitor specification during zebrafish embryonic development.
{"title":"Pharyngeal pouches provide a niche microenvironment for arch artery progenitor specification","authors":"Aihua Mao, Mingming Zhang, Linwei Li, Jie Liu, Guozhu Ning, Yu Cao, Qiang Wang","doi":"10.1101/2020.05.07.083493","DOIUrl":"https://doi.org/10.1101/2020.05.07.083493","url":null,"abstract":"ABSTRACT The paired pharyngeal arch arteries (PAAs) are transient blood vessels connecting the heart with the dorsal aorta during embryogenesis. Although PAA malformations often occur along with pharyngeal pouch defects, the functional interaction between these adjacent tissues remains largely unclear. Here, we report that pharyngeal pouches are essential for PAA progenitor specification in zebrafish embryos. We reveal that the segmentation of pharyngeal pouches coincides spatiotemporally with the emergence of PAA progenitor clusters. These pouches physically associate with pharyngeal mesoderm in discrete regions and provide a niche microenvironment for PAA progenitor commitment by expressing BMP proteins. Specifically, pouch-derived BMP2a and BMP5 are the primary niche cues responsible for activating the BMP/Smad pathway in pharyngeal mesoderm, thereby promoting progenitor specification. In addition, BMP2a and BMP5 play an inductive function in the expression of the cloche gene npas4l in PAA progenitors. cloche mutants exhibit a striking failure to specify PAA progenitors and display ectopic expression of head muscle markers in the pharyngeal mesoderm. Therefore, our results support a crucial role for pharyngeal pouches in establishing a progenitor niche for PAA morphogenesis via BMP2a/5 expression. Summary: Pharyngeal pouch-derived BMP2a and BMP5 are the key niche cues that induce arch artery progenitor specification during zebrafish embryonic development.","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"90 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"73555639","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2020-01-01DOI: 10.1101/2020.01.09.900498
Dylan M. Parker, Lindsay P. Winkenbach, Sam Boyson, Matthew N. Saxton, Camryn Daidone, Zainab A. Al-Mazaydeh, M. Nishimura, F. Mueller, Erin Osborne Nishimura
ABSTRACT Caenorhabditis elegans early embryos generate cell-specific transcriptomes despite lacking active transcription, thereby presenting an opportunity to study mechanisms of post-transcriptional regulatory control. We observed that some cell-specific mRNAs accumulate non-homogenously within cells, localizing to membranes, P granules (associated with progenitor germ cells in the P lineage) and P-bodies (associated with RNA processing). The subcellular distribution of transcripts differed in their dependence on 3′UTRs and RNA binding proteins, suggesting diverse regulatory mechanisms. Notably, we found strong but imperfect correlations between low translational status and P granule localization within the progenitor germ lineage. By uncoupling translation from mRNA localization, we untangled a long-standing question: Are mRNAs directed to P granules to be translationally repressed, or do they accumulate there as a consequence of this repression? We found that translational repression preceded P granule localization and could occur independently of it. Further, disruption of translation was sufficient to send homogenously distributed mRNAs to P granules. These results implicate transcriptional repression as a means to deliver essential maternal transcripts to the progenitor germ lineage for later translation. Summary: Maternally loaded mRNAs localize non-homogenously within Caenorhabditis elegans early embryos, correlating with their translational status and lineage-specific fates
{"title":"mRNA localization is linked to translation regulation in the Caenorhabditis elegans germ lineage","authors":"Dylan M. Parker, Lindsay P. Winkenbach, Sam Boyson, Matthew N. Saxton, Camryn Daidone, Zainab A. Al-Mazaydeh, M. Nishimura, F. Mueller, Erin Osborne Nishimura","doi":"10.1101/2020.01.09.900498","DOIUrl":"https://doi.org/10.1101/2020.01.09.900498","url":null,"abstract":"ABSTRACT Caenorhabditis elegans early embryos generate cell-specific transcriptomes despite lacking active transcription, thereby presenting an opportunity to study mechanisms of post-transcriptional regulatory control. We observed that some cell-specific mRNAs accumulate non-homogenously within cells, localizing to membranes, P granules (associated with progenitor germ cells in the P lineage) and P-bodies (associated with RNA processing). The subcellular distribution of transcripts differed in their dependence on 3′UTRs and RNA binding proteins, suggesting diverse regulatory mechanisms. Notably, we found strong but imperfect correlations between low translational status and P granule localization within the progenitor germ lineage. By uncoupling translation from mRNA localization, we untangled a long-standing question: Are mRNAs directed to P granules to be translationally repressed, or do they accumulate there as a consequence of this repression? We found that translational repression preceded P granule localization and could occur independently of it. Further, disruption of translation was sufficient to send homogenously distributed mRNAs to P granules. These results implicate transcriptional repression as a means to deliver essential maternal transcripts to the progenitor germ lineage for later translation. Summary: Maternally loaded mRNAs localize non-homogenously within Caenorhabditis elegans early embryos, correlating with their translational status and lineage-specific fates","PeriodicalId":77105,"journal":{"name":"Development (Cambridge, England). Supplement","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2020-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83670523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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