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1.
J Vis Exp ; (185)2022 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-35913197

RESUMO

The first steps of heart development imply drastic changes in cell behavior and differentiation. While analysis of fixed embryos allows studying in detail specific developmental stages in a still snapshot, live imaging captures dynamic morphogenetic events, such as cell migration, shape changes, and differentiation, by imaging the embryo as it develops. This complements fixed analysis and expands the understanding of how organs develop during embryogenesis. Despite its advantages, live imaging is rarely used in mouse models because of its technical challenges. Early mouse embryos are sensitive when cultured ex vivo and require efficient handling. To facilitate a broader use of live imaging in mouse developmental research, this paper presents a detailed protocol for two-photon live microscopy that allows long-term acquisition in mouse embryos. In addition to the protocol, tips are provided on embryo handling and culture optimization. This will help understand key events in early mouse organogenesis, enhancing the understanding of cardiovascular progenitor biology.


Assuntos
Embrião de Mamíferos , Desenvolvimento Embrionário , Animais , Embrião de Mamíferos/diagnóstico por imagem , Coração/diagnóstico por imagem , Camundongos , Microscopia/métodos , Organogênese
2.
Nat Genet ; 54(7): 1037-1050, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35789323

RESUMO

Zebrafish, a popular organism for studying embryonic development and for modeling human diseases, has so far lacked a systematic functional annotation program akin to those in other animal models. To address this, we formed the international DANIO-CODE consortium and created a central repository to store and process zebrafish developmental functional genomic data. Our data coordination center ( https://danio-code.zfin.org ) combines a total of 1,802 sets of unpublished and re-analyzed published genomic data, which we used to improve existing annotations and show its utility in experimental design. We identified over 140,000 cis-regulatory elements throughout development, including classes with distinct features dependent on their activity in time and space. We delineated the distinct distance topology and chromatin features between regulatory elements active during zygotic genome activation and those active during organogenesis. Finally, we matched regulatory elements and epigenomic landscapes between zebrafish and mouse and predicted functional relationships between them beyond sequence similarity, thus extending the utility of zebrafish developmental genomics to mammals.


Assuntos
Bases de Dados Genéticas , Regulação da Expressão Gênica no Desenvolvimento , Genoma , Genômica , Sequências Reguladoras de Ácido Nucleico , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Cromatina/genética , Genoma/genética , Humanos , Camundongos , Anotação de Sequência Molecular , Organogênese/genética , Sequências Reguladoras de Ácido Nucleico/genética , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética
3.
PLoS Genet ; 18(7): e1009765, 2022 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-35839257

RESUMO

Hyaluronan (HA) is a major extracellular matrix component whose tissue levels are dynamically regulated during embryonic development. Although the synthesis of HA has been shown to exert a substantial influence on embryonic morphogenesis, the functional importance of the catabolic aspect of HA turnover is poorly understood. Here, we demonstrate that the transmembrane hyaluronidase TMEM2 plays an essential role in neural crest development and the morphogenesis of neural crest derivatives, as evidenced by the presence of severe craniofacial abnormalities in Wnt1-Cre-mediated Tmem2 knockout (Tmem2CKO) mice. Neural crest cells (NCCs) are a migratory population of cells that gives rise to diverse cell lineages, including the craniofacial complex, the peripheral nervous system, and part of the heart. Analysis of Tmem2 expression during NCC formation and migration reveals that Tmem2 is expressed at the site of NCC delamination and in emigrating Sox9-positive NCCs. In Tmem2CKO embryos, the number of NCCs emigrating from the neural tube is greatly reduced. Furthermore, linage tracing reveals that the number of NCCs traversing the ventral migration pathway and the number of post-migratory neural crest derivatives are both significantly reduced in a Tmem2CKO background. In vitro studies using Tmem2-depleted mouse O9-1 neural crest cells demonstrate that Tmem2 expression is essential for the ability of these cells to form focal adhesions on and to migrate into HA-containing substrates. Additionally, we show that Tmem2-deficient NCCs exhibit increased apoptotic cell death in NCC-derived tissues, an observation that is corroborated by in vitro experiments using O9-1 cells. Collectively, our data demonstrate that TMEM2-mediated HA degradation plays an essential role in normal neural crest development. This study reveals the hitherto unrecognized functional importance of HA degradation in embryonic development and highlights the pivotal role of Tmem2 in the developmental process.


Assuntos
Hialuronoglucosaminidase , Crista Neural , Animais , Diferenciação Celular , Movimento Celular/genética , Proteínas de Membrana/genética , Camundongos , Camundongos Knockout , Organogênese
4.
Dev Cell ; 57(14): 1742-1757.e5, 2022 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-35803279

RESUMO

Alveolar epithelial cell fate decisions drive lung development and regeneration. Using transcriptomic and epigenetic profiling coupled with genetic mouse and organoid models, we identified the transcription factor Klf5 as an essential determinant of alveolar epithelial cell fate across the lifespan. We show that although dispensable for both adult alveolar epithelial type 1 (AT1) and alveolar epithelial type 2 (AT2) cell homeostasis, Klf5 enforces AT1 cell lineage fidelity during development. Using infectious and non-infectious models of acute respiratory distress syndrome, we demonstrate that Klf5 represses AT2 cell proliferation and enhances AT2-AT1 cell differentiation in a spatially restricted manner during lung regeneration. Moreover, ex vivo organoid assays identify that Klf5 reduces AT2 cell sensitivity to inflammatory signaling to drive AT2-AT1 cell differentiation. These data define the roll of a major transcriptional regulator of AT1 cell lineage commitment and of the AT2 cell response to inflammatory crosstalk during lung regeneration.


Assuntos
Células Epiteliais Alveolares , Pulmão , Células Epiteliais Alveolares/metabolismo , Animais , Diferenciação Celular/fisiologia , Linhagem da Célula , Fatores de Transcrição Kruppel-Like/genética , Fatores de Transcrição Kruppel-Like/metabolismo , Camundongos , Organogênese , Fatores de Transcrição/metabolismo
5.
Sci Rep ; 12(1): 12498, 2022 Jul 21.
Artigo em Inglês | MEDLINE | ID: mdl-35864120

RESUMO

Development of the pancreas is driven by an intrinsic program coordinated with signals from other cell types in the epithelial environment. These intercellular communications have been so far challenging to study because of the low concentration, localized production and diversity of the signals released. Here, we combined scRNAseq data with a computational interactomic approach to identify signals involved in the reciprocal interactions between the various cell types of the developing pancreas. This in silico approach yielded 40,607 potential ligand-target interactions between the different main pancreatic cell types. Among this vast network of interactions, we focused on three ligands potentially involved in communications between epithelial and endothelial cells. BMP7 and WNT7B, expressed by pancreatic epithelial cells and predicted to target endothelial cells, and SEMA6D, involved in the reverse interaction. In situ hybridization confirmed the localized expression of Bmp7 in the pancreatic epithelial tip cells and of Wnt7b in the trunk cells. On the contrary, Sema6d was enriched in endothelial cells. Functional experiments on ex vivo cultured pancreatic explants indicated that tip cell-produced BMP7 limited development of endothelial cells. This work identified ligands with a restricted tissular and cellular distribution and highlighted the role of BMP7 in the intercellular communications contributing to vessel development and organization during pancreas organogenesis.


Assuntos
Células Endoteliais , Organogênese , Diferenciação Celular/fisiologia , Células Endoteliais/metabolismo , Ligantes , Organogênese/fisiologia , Pâncreas/metabolismo
6.
Nat Commun ; 13(1): 4148, 2022 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-35851388

RESUMO

Pancreatic differentiation from human pluripotent stem cells (hPSCs) provides promising avenues for investigating development and treating diseases. N6-methyladenosine (m6A) is the most prevalent internal messenger RNA (mRNA) modification and plays pivotal roles in regulation of mRNA metabolism, while its functions remain elusive. Here, we profile the dynamic landscapes of m6A transcriptome-wide during pancreatic differentiation. Next, we generate knockout hPSC lines of the major m6A demethylase ALKBH5, and find that ALKBH5 plays significant regulatory roles in pancreatic organogenesis. Mechanistic studies reveal that ALKBH5 deficiency reduces the mRNA stability of key pancreatic transcription factors in an m6A and YTHDF2-dependent manner. We further identify that ALKBH5 cofactor α-ketoglutarate can be applied to enhance differentiation. Collectively, our findings identify ALKBH5 as an essential regulator of pancreatic differentiation and highlight that m6A modification-mediated mRNA metabolism presents an important layer of regulation during cell-fate specification and holds great potentials for translational applications.


Assuntos
Homólogo AlkB 5 da RNA Desmetilase , Estabilidade de RNA , Adenosina/análogos & derivados , Homólogo AlkB 5 da RNA Desmetilase/metabolismo , Humanos , Organogênese/genética , Estabilidade de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Fatores de Transcrição/genética
7.
Circulation ; 146(1): 48-63, 2022 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-35652354

RESUMO

BACKGROUND: Certain nonmammalian species such as zebrafish have an elevated capacity for innate heart regeneration. Understanding how heart regeneration occurs in these contexts can help illuminate cellular and molecular events that can be targets for heart failure prevention or treatment. The epicardium, a mesothelial tissue layer that encompasses the heart, is a dynamic structure that is essential for cardiac regeneration in zebrafish. The extent to which different cell subpopulations or states facilitate heart regeneration requires research attention. METHODS: To dissect epicardial cell states and associated proregenerative functions, we performed single-cell RNA sequencing and identified 7 epicardial cell clusters in adult zebrafish, 3 of which displayed enhanced cell numbers during regeneration. We identified paralogs of hapln1 as factors associated with the extracellular matrix and largely expressed in cluster 1. We assessed HAPLN1 expression in published single-cell RNA sequencing data sets from different stages and injury states of murine and human hearts, and we performed molecular genetics to determine the requirements for hapln1-expressing cells and functions of each hapln1 paralog. RESULTS: A particular cluster of epicardial cells had the strongest association with regeneration and was marked by expression of hapln1a and hapln1b. The hapln1 paralogs are expressed in epicardial cells that enclose dedifferentiated and proliferating cardiomyocytes during regeneration. Induced genetic depletion of hapln1-expressing cells or genetic inactivation of hapln1b altered deposition of the key extracellular matrix component hyaluronic acid, disrupted cardiomyocyte proliferation, and inhibited heart regeneration. We also found that hapln1-expressing epicardial cells first emerge at the juvenile stage, when they associate with and are required for focused cardiomyocyte expansion events that direct maturation of the ventricular wall. CONCLUSIONS: Our findings identify a subset of epicardial cells that emerge in postembryonic zebrafish and sponsor regions of active cardiomyogenesis during cardiac growth and regeneration. We provide evidence that, as the heart achieves its mature structure, these cells facilitate hyaluronic acid deposition to support formation of the compact muscle layer of the ventricle. They are also required, along with the function of hapln1b paralog, in the production and organization of hyaluronic acid-containing matrix in cardiac injury sites, enabling normal cardiomyocyte proliferation and muscle regeneration.


Assuntos
Proteínas da Matriz Extracelular , Coração , Miócitos Cardíacos , Proteoglicanas , Animais , Proliferação de Células , Proteínas da Matriz Extracelular/metabolismo , Coração/fisiologia , Humanos , Ácido Hialurônico/metabolismo , Camundongos , Miócitos Cardíacos/metabolismo , Organogênese , Proteoglicanas/metabolismo , Regeneração/fisiologia , Peixe-Zebra/genética , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo
8.
Dev Cell ; 57(13): 1566-1581.e7, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35714603

RESUMO

Alveolar formation increases the surface area for gas exchange. A molecular understanding of alveologenesis remains incomplete. Here, we show that the autonomic nerve and alveolar myofibroblast form a functional unit in mice. Myofibroblasts secrete neurotrophins to promote neurite extension/survival, whereas neurotransmitters released from autonomic terminals are necessary for myofibroblast proliferation and migration, a key step in alveologenesis. This establishes a functional link between autonomic innervation and alveolar formation. We also discover that planar cell polarity (PCP) signaling employs a Wnt-Fz/Ror-Vangl cascade to regulate the cytoskeleton and neurotransmitter trafficking/release from the terminals of autonomic nerves. This represents a new aspect of PCP signaling in conferring cellular properties. Together, these studies offer molecular insight into how autonomic activity controls alveolar formation. Our work also illustrates the fundamental principle of how two tissues (e.g., nerves and lungs) interact to build alveoli at the organismal level.


Assuntos
Miofibroblastos , Alvéolos Pulmonares , Animais , Vias Autônomas , Pulmão , Mamíferos , Camundongos , Organogênese
9.
Nutrition ; 101: 111682, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-35660498

RESUMO

OBJECTIVES: The present study aimed to evaluate the effects of maternal protein restriction during pregnancy on the lungs of 1-d and 31-d old offspring of C57BL/6 mice. METHODS: The C57BL/6 mice (8-10 wk) were used for breeding. After pregnancy confirmation, female mice were randomly divided into a control group (CG) receiving a standard diet (22% protein) and a protein-restriction group (PRG) receiving a low-protein diet (6% protein). In the low-protein diet, protein was replaced by carbohydrate. After parturition, female mice that received the low-protein diet were fed the standard diet. Male offspring were euthanized 1 d and 31 d after birth for subsequent analysis. We evaluated the effects of a protein-restricted diet during gestation in pulmonary organogenesis, lung oxidative stress, and pulmonary inflammatory response of the offspring. RESULTS: PRG mice 1 d after birth showed lower body and lung mass, length, relative mass, lung density, and erythrocyte count compared with CG mice. There was an increase in alveolar airspace density and a higher mean linear intercept (Lm), greater oxidative damage, and inflammation in PRG mice compared with CG mice. At 31 d after birth, PRG mice had lower body mass, length, and lung mass values compared with CG mice. PRG mice showed greater recruitment of inflammatory cells to the airways. In addition, there was increased collagen deposition in the lungs, altered inflammatory mediators, and greater oxidative damage compared with CG mice. CONCLUSIONS: Protein restriction during pregnancy reduces the body weight of offspring and promotes inflammation and oxidative stress, resulting in a simplification of the lung structure.


Assuntos
Dieta com Restrição de Proteínas , Efeitos Tardios da Exposição Pré-Natal , Animais , Dieta com Restrição de Proteínas/efeitos adversos , Feminino , Humanos , Inflamação , Pulmão , Masculino , Fenômenos Fisiológicos da Nutrição Materna , Camundongos , Camundongos Endogâmicos C57BL , Organogênese , Estresse Oxidativo , Gravidez
10.
Cell Stem Cell ; 29(6): 871-872, 2022 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-35659871

RESUMO

In this issue, Ben-Moshe et al. (2022) use spatiotemporally resolved single-cell and spatial transcriptomic profiling to dissect the multicellular dynamics enabling zonal liver regeneration. They highlight how pan-zonal compensatory hepatocyte proliferation, transient reprogramming of peri-injury hepatocytes, and concerted zonated action of different liver cell types orchestrate the healing process.


Assuntos
Hepatócitos , Regeneração Hepática , Proliferação de Células , Perfilação da Expressão Gênica , Hepatócitos/metabolismo , Fígado/metabolismo , Organogênese
11.
Development ; 149(13)2022 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-35771637

RESUMO

Rashmi Priya is a Group Leader at The Francis Crick Institute in London, UK. Her research combines genetic, cell biological and biophysical approaches to understand the complex morphogenetic events of organogenesis, using the zebrafish heart as a model system. We met Rashmi at the Crick to learn how she got started as a researcher, and to discuss the challenges of starting a lab in the middle of a global pandemic.


Assuntos
Pesquisadores , Peixe-Zebra , Animais , Biofísica , Humanos , Modelos Biológicos , Organogênese , Peixe-Zebra/genética
12.
Cells ; 11(12)2022 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-35741008

RESUMO

Primary cilia are crucial for normal cardiac organogenesis via the formation of cyto-architectural, anatomical, and physiological boundaries in the developing heart and outflow tract. These tiny, plasma membrane-bound organelles function in a sensory-integrative capacity, interpreting both the intra- and extra-cellular environments and directing changes in gene expression responses to promote, prevent, and modify cellular proliferation and differentiation. One distinct feature of this organelle is its involvement in the propagation of a variety of signaling cascades, most notably, the Hedgehog cascade. Three ligands, Sonic, Indian, and Desert hedgehog, function as growth factors that are most commonly dependent on the presence of intact primary cilia, where the Hedgehog receptors Patched-1 and Smoothened localize directly within or at the base of the ciliary axoneme. Hedgehog signaling functions to mediate many cell behaviors that are critical for normal embryonic tissue/organ development. However, inappropriate activation and/or upregulation of Hedgehog signaling in postnatal and adult tissue is known to initiate oncogenesis, as well as the pathogenesis of other diseases. The focus of this review is to provide an overview describing the role of Hedgehog signaling and its dependence upon the primary cilium in the cell types that are most essential for mammalian heart development. We outline the breadth of developmental defects and the consequential pathologies resulting from inappropriate changes to Hedgehog signaling, as it pertains to congenital heart disease and general cardiac pathophysiology.


Assuntos
Cílios , Proteínas Hedgehog , Animais , Cílios/metabolismo , Coração , Proteínas Hedgehog/metabolismo , Mamíferos/metabolismo , Organogênese , Transdução de Sinais/fisiologia
13.
Cells ; 11(12)2022 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-35741098

RESUMO

TNF and LTα are structurally related cytokines of the TNF superfamily. Their genes are located in close proximity to each other and to the Ltb gene within the TNF/LT locus inside MHC. Unlike Ltb, transcription of Tnf and of Lta is tightly controlled, with the Tnf gene being an immediate early gene that is rapidly induced in response to various inflammatory stimuli. Genes of the TNF/LT locus play a crucial role in lymphoid tissue organogenesis, although some aspects of their specific contribution remain controversial. Here, we present new findings and discuss the distinct contribution of TNF produced by ILC3 cells to Peyer's patch organogenesis.


Assuntos
Linfotoxina-alfa , Nódulos Linfáticos Agregados , Animais , Tecido Linfoide , Camundongos , Camundongos Knockout , Organogênese/genética , Fatores de Necrose Tumoral/metabolismo
14.
Cells ; 11(12)2022 06 20.
Artigo em Inglês | MEDLINE | ID: mdl-35741102

RESUMO

Insulin-like growth factor (IGF) signaling controls the development and growth of many organs, including the lung. Loss of function of Igf1 or its receptor Igf1r impairs lung development and leads to neonatal respiratory distress in mice. Although many components of the IGF signaling pathway have shown to be dysregulated in idiopathic pulmonary fibrosis (IPF), the expression pattern of such components in different cellular compartments of the developing and/or fibrotic lung has been elusive. In this study, we provide a comprehensive transcriptional profile for such signaling components during embryonic lung development in mice, bleomycin-induced pulmonary fibrosis in mice and in human IPF lung explants. During late gestation, we found that Igf1 is upregulated in parallel to Igf1r downregulation in the lung mesenchyme. Lung tissues derived from bleomycin-treated mice and explanted IPF lungs revealed upregulation of IGF1 in parallel to downregulation of IGF1R, in addition to upregulation of several IGF binding proteins (IGFBPs) in lung fibrosis. Finally, treatment of IPF lung fibroblasts with recombinant IGF1 led to myogenic differentiation. Our data serve as a resource for the transcriptional profile of IGF signaling components and warrant further research on the involvement of this pathway in both lung development and pulmonary disease.


Assuntos
Fibrose Pulmonar Idiopática , Animais , Bleomicina/farmacologia , Feminino , Fibrose Pulmonar Idiopática/induzido quimicamente , Fibrose Pulmonar Idiopática/genética , Fibrose Pulmonar Idiopática/metabolismo , Proteínas de Ligação a Fator de Crescimento Semelhante a Insulina , Pulmão/metabolismo , Camundongos , Organogênese , Gravidez , Transdução de Sinais
15.
Development ; 149(12)2022 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-35726824

RESUMO

Prostate organogenesis begins during embryonic development and continues through puberty when the prostate becomes an important exocrine gland of the male reproductive system. The specification and growth of the prostate is regulated by androgens and is largely a result of cell-cell communication between the epithelium and mesenchyme. The fields of developmental and cancer biology have long been interested in prostate organogenesis because of its relevance for understanding prostate diseases, and research has expanded in recent years with the advent of novel technologies, including genetic-lineage tracing, single-cell RNA sequencing and organoid culture methods, that have provided important insights into androgen regulation, epithelial cell origins and cellular heterogeneity. We discuss these findings, putting them into context with what is currently known about prostate organogenesis.


Assuntos
Organogênese , Próstata , Androgênios , Células Epiteliais , Epitélio , Humanos , Masculino , Mesoderma , Organogênese/genética
17.
PLoS Comput Biol ; 18(6): e1010142, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35666714

RESUMO

Embryonic heart development is a mechanosensitive process, where specific fluid forces are needed for the correct development, and abnormal mechanical stimuli can lead to malformations. It is thus important to understand the nature of embryonic heart fluid forces. However, the fluid dynamical behaviour close to the embryonic endocardial surface is very sensitive to the geometry and motion dynamics of fine-scale cardiac trabecular surface structures. Here, we conducted image-based computational fluid dynamics (CFD) simulations to quantify the fluid mechanics associated with the zebrafish embryonic heart trabeculae. To capture trabecular geometric and motion details, we used a fish line that expresses fluorescence at the endocardial cell membrane, and high resolution 3D confocal microscopy. Our endocardial wall shear stress (WSS) results were found to exceed those reported in existing literature, which were estimated using myocardial rather than endocardial boundaries. By conducting simulations of single intra-trabecular spaces under varied scenarios, where the translational or deformational motions (caused by contraction) were removed, we found that a squeeze flow effect was responsible for most of the WSS magnitude in the intra-trabecular spaces, rather than the shear interaction with the flow in the main ventricular chamber. We found that trabecular structures were responsible for the high spatial variability of the magnitude and oscillatory nature of WSS, and for reducing the endocardial deformational burden. We further found cells attached to the endocardium within the intra-trabecular spaces, which were likely embryonic hemogenic cells, whose presence increased endocardial WSS. Overall, our results suggested that a complex multi-component consideration of both anatomic features and motion dynamics were needed to quantify the trabeculated embryonic heart fluid mechanics.


Assuntos
Modelos Cardiovasculares , Peixe-Zebra , Animais , Coração , Hidrodinâmica , Organogênese , Estresse Mecânico
18.
PLoS Genet ; 18(6): e1009978, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35666766

RESUMO

The sumoylation (SUMO) pathway is involved in a variety of processes during C. elegans development, such as gonadal and vulval fate specification, cell cycle progression and maintenance of chromosome structure. The ubiquitous expression and pleiotropic effects have made it difficult to dissect the tissue-specific functions of the SUMO pathway and identify its target proteins. To overcome these challenges, we have established tools to block protein sumoylation and degrade sumoylated target proteins in a tissue-specific and temporally controlled manner. We employed the auxin-inducible protein degradation system (AID) to down-regulate the SUMO E3 ligase GEI-17 or the SUMO ortholog SMO-1, either in the vulval precursor cells (VPCs) or in the gonadal anchor cell (AC). Our results indicate that the SUMO pathway acts in multiple tissues to control different aspects of vulval development, such as AC positioning, basement membrane (BM) breaching, VPC fate specification and morphogenesis. Inhibition of protein sumoylation in the VPCs resulted in abnormal toroid formation and ectopic cell fusions during vulval morphogenesis. In particular, sumoylation of the ETS transcription factor LIN-1 at K169 is necessary for the proper contraction of the ventral vulA toroids. Thus, the SUMO pathway plays several distinct roles throughout vulval development.


Assuntos
Proteínas de Caenorhabditis elegans , Caenorhabditis elegans , Animais , Caenorhabditis elegans/genética , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Feminino , Organogênese , Sumoilação/genética , Fatores de Transcrição/genética , Vulva
19.
Dev Cell ; 57(13): 1598-1614.e8, 2022 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-35679862

RESUMO

The human respiratory epithelium is derived from a progenitor cell in the distal buds of the developing lung. These "bud tip progenitors" are regulated by reciprocal signaling with surrounding mesenchyme; however, mesenchymal heterogeneity and function in the developing human lung are poorly understood. We interrogated single-cell RNA sequencing data from multiple human lung specimens and identified a mesenchymal cell population present during development that is highly enriched for expression of the WNT agonist RSPO2, and we found that the adjacent bud tip progenitors are enriched for the RSPO2 receptor LGR5. Functional experiments using organoid models, explant cultures, and FACS-isolated RSPO2+ mesenchyme show that RSPO2 is a critical niche cue that potentiates WNT signaling in bud tip progenitors to support their maintenance and multipotency.


Assuntos
Células-Tronco Mesenquimais , Organogênese , Humanos , Pulmão , Organoides , Via de Sinalização Wnt
20.
Cells ; 11(11)2022 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-35681469

RESUMO

The development of the embryonic lung demands complex endodermal-mesodermal interactions, which are regulated by a variety of signaling proteins. Hedgehog (Hh) signaling is vital for lung development. It plays a key regulatory role during several morphogenic mechanisms, such as cell growth, differentiation, migration, and persistence of cells. On the other hand, abnormal expression or loss of regulation of Hh signaling leads to airway asthmatic remodeling, which is characterized by cellular matrix modification in the respiratory system, goblet cell hyperplasia, deposition of collagen, epithelial cell apoptosis, proliferation, and activation of fibroblasts. Hh also targets some of the pathogens and seems to have a significant function in tissue repairment and immune-related disorders. Similarly, aberrant Hh signaling expression is critically associated with the etiology of a variety of other airway lung diseases, mainly, bronchial or tissue fibrosis, lung cancer, and pulmonary arterial hypertension, suggesting that controlled regulation of Hh signaling is crucial to retain healthy lung functioning. Moreover, shreds of evidence imply that the Hh signaling pathway links to lung organogenesis and asthmatic airway remodeling. Here, we compiled all up-to-date investigations linked with the role of Hh signaling in the development of lungs as well as the attribution of Hh signaling in impairment of lung expansion, airway remodeling, and immune response. In addition, we included all current investigational and therapeutic approaches to treat airway asthmatic remodeling and immune system pathway diseases.


Assuntos
Remodelação das Vias Aéreas , Asma , Asma/tratamento farmacológico , Proteínas Hedgehog/metabolismo , Humanos , Pulmão/metabolismo , Organogênese , Transdução de Sinais
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