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1.
Development ; 148(19)2021 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-34486668

RESUMO

Birth defects result from interactions between genetic and environmental factors, but the mechanisms remain poorly understood. We find that mutations and teratogens interact in predictable ways to cause birth defects by changing target cell sensitivity to Hedgehog (Hh) ligands. These interactions converge on a membrane protein complex, the MMM complex, that promotes degradation of the Hh transducer Smoothened (SMO). Deficiency of the MMM component MOSMO results in elevated SMO and increased Hh signaling, causing multiple birth defects. In utero exposure to a teratogen that directly inhibits SMO reduces the penetrance and expressivity of birth defects in Mosmo-/- embryos. Additionally, tissues that develop normally in Mosmo-/- embryos are refractory to the teratogen. Thus, changes in the abundance of the protein target of a teratogen can change birth defect outcomes by quantitative shifts in Hh signaling. Consequently, small molecules that re-calibrate signaling strength could be harnessed to rescue structural birth defects.


Assuntos
Anormalidades Induzidas por Medicamentos/genética , Interação Gene-Ambiente , Proteínas Hedgehog/metabolismo , Penetrância , Animais , Células Cultivadas , Células HEK293 , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Células NIH 3T3 , Transdução de Sinais , Receptor Smoothened/genética , Receptor Smoothened/metabolismo
2.
Nature ; 509(7500): 371-5, 2014 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-24739965

RESUMO

The mammalian lung is a highly branched network in which the distal regions of the bronchial tree transform during development into a densely packed honeycomb of alveolar air sacs that mediate gas exchange. Although this transformation has been studied by marker expression analysis and fate-mapping, the mechanisms that control the progression of lung progenitors along distinct lineages into mature alveolar cell types are still incompletely known, in part because of the limited number of lineage markers and the effects of ensemble averaging in conventional transcriptome analysis experiments on cell populations. Here we show that single-cell transcriptome analysis circumvents these problems and enables direct measurement of the various cell types and hierarchies in the developing lung. We used microfluidic single-cell RNA sequencing (RNA-seq) on 198 individual cells at four different stages encompassing alveolar differentiation to measure the transcriptional states which define the developmental and cellular hierarchy of the distal mouse lung epithelium. We empirically classified cells into distinct groups by using an unbiased genome-wide approach that did not require a priori knowledge of the underlying cell types or the previous purification of cell populations. The results confirmed the basic outlines of the classical model of epithelial cell-type diversity in the distal lung and led to the discovery of many previously unknown cell-type markers, including transcriptional regulators that discriminate between the different populations. We reconstructed the molecular steps during maturation of bipotential progenitors along both alveolar lineages and elucidated the full life cycle of the alveolar type 2 cell lineage. This single-cell genomics approach is applicable to any developing or mature tissue to robustly delineate molecularly distinct cell types, define progenitors and lineage hierarchies, and identify lineage-specific regulatory factors.


Assuntos
Linhagem da Célula/genética , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Pulmão/citologia , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Animais , Brônquios/citologia , Diferenciação Celular/genética , Células Epiteliais/classificação , Feminino , Marcadores Genéticos , Genoma/genética , Genômica , Pulmão/embriologia , Camundongos , Camundongos Endogâmicos C57BL , Alvéolos Pulmonares/citologia , Troca Gasosa Pulmonar , Células-Tronco/citologia , Transcriptoma/genética
3.
Development ; 140(20): 4277-86, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24048590

RESUMO

The transcriptional control of primary cilium formation and ciliary motility are beginning to be understood, but little is known about the transcriptional programs that control cilium number and other structural and functional specializations. One of the most intriguing ciliary specializations occurs in multiciliated cells (MCCs), which amplify their centrioles to nucleate hundreds of cilia per cell, instead of the usual monocilium. Here we report that the transcription factor MYB, which promotes S phase and drives cycling of a variety of progenitor cells, is expressed in postmitotic epithelial cells of the mouse airways and ependyma destined to become MCCs. MYB is expressed early in multiciliogenesis, as progenitors exit the cell cycle and amplify their centrioles, then switches off as MCCs mature. Conditional inactivation of Myb in the developing airways blocks or delays centriole amplification and expression of FOXJ1, a transcription factor that controls centriole docking and ciliary motility, and airways fail to become fully ciliated. We provide evidence that MYB acts in a conserved pathway downstream of Notch signaling and multicilin, a protein related to the S-phase regulator geminin, and upstream of FOXJ1. MYB can activate endogenous Foxj1 expression and stimulate a cotransfected Foxj1 reporter in heterologous cells, and it can drive the complete multiciliogenesis program in Xenopus embryonic epidermis. We conclude that MYB has an early, crucial and conserved role in multiciliogenesis, and propose that it promotes a novel S-like phase in which centriole amplification occurs uncoupled from DNA synthesis, and then drives later steps of multiciliogenesis through induction of Foxj1.


Assuntos
Centríolos/metabolismo , Cílios/metabolismo , Fatores de Transcrição Forkhead/metabolismo , Proteínas Proto-Oncogênicas c-myb/metabolismo , Animais , Encéfalo/embriologia , Encéfalo/metabolismo , Diferenciação Celular , Movimento Celular , Células Cultivadas , Centríolos/genética , Cílios/genética , Epêndima/embriologia , Epêndima/metabolismo , Células Epiteliais/metabolismo , Fatores de Transcrição Forkhead/biossíntese , Pulmão/embriologia , Pulmão/metabolismo , Camundongos/embriologia , Camundongos Transgênicos , Transdução de Sinais , Traqueia/embriologia , Traqueia/metabolismo , Xenopus laevis/embriologia
4.
J Clin Invest ; 130(10): 5562-5575, 2020 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-32673288

RESUMO

Pathologic lymphatic remodeling in lymphedema evolves during periods of tissue inflammation and hypoxia through poorly defined processes. In human and mouse lymphedema, there is a significant increase of hypoxia inducible factor 1 α (HIF-1α), but a reduction of HIF-2α protein expression in lymphatic endothelial cells (LECs). We questioned whether dysregulated expression of these transcription factors contributes to disease pathogenesis and found that LEC-specific deletion of Hif2α exacerbated lymphedema pathology. Even without lymphatic vascular injury, the loss of LEC-specific Hif2α caused anatomic pathology and a functional decline in fetal and adult mice. These findings suggest that HIF-2α is an important mediator of lymphatic health. HIF-2α promoted protective phosphorylated TIE2 (p-TIE2) signaling in LECs, a process also replicated by upregulating TIE2 signaling through adenovirus-mediated angiopoietin-1 (Angpt1) gene therapy. Our study suggests that HIF-2α normally promotes healthy lymphatic homeostasis and raises the exciting possibility that restoring HIF-2α pathways in lymphedema could mitigate long-term pathology and disability.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/deficiência , Sistema Linfático/metabolismo , Sistema Linfático/patologia , Linfedema/metabolismo , Linfedema/patologia , Angiopoietina-1/genética , Angiopoietina-1/uso terapêutico , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Modelos Animais de Doenças , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Feminino , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Sistema Linfático/embriologia , Linfedema/etiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fosforilação , Gravidez , Receptor TIE-2/metabolismo , Transdução de Sinais
5.
Science ; 346(6211): 1258810, 2014 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-25395543

RESUMO

Most vertebrate organs are composed of epithelium surrounded by support and stromal tissues formed from mesenchyme cells, which are not generally thought to form organized progenitor pools. Here, we use clonal cell labeling with multicolor reporters to characterize individual mesenchymal progenitors in the developing mouse lung. We observe a diversity of mesenchymal progenitor populations with different locations, movements, and lineage boundaries. Airway smooth muscle (ASM) progenitors map exclusively to mesenchyme ahead of budding airways. Progenitors recruited from these tip pools differentiate into ASM around airway stalks; flanking stalk mesenchyme can be induced to form an ASM niche by a lateral bud or by an airway tip plus focal Wnt signal. Thus, mesenchymal progenitors can be organized into localized and carefully controlled domains that rival epithelial progenitor niches in regulatory sophistication.


Assuntos
Pulmão/crescimento & desenvolvimento , Células-Tronco Mesenquimais/fisiologia , Nicho de Células-Tronco/fisiologia , Animais , Diferenciação Celular , Linhagem da Célula , Movimento Celular , Proliferação de Células , Rastreamento de Células , Células Clonais , Pulmão/citologia , Células-Tronco Mesenquimais/citologia , Camundongos , Camundongos Transgênicos , Análise de Célula Única/métodos , Via de Sinalização Wnt
6.
Dev Cell ; 23(3): 482-93, 2012 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-22975322

RESUMO

Some of the most serious diseases involve altered size and structure of the arterial wall. Elucidating how arterial walls are built could aid understanding of these diseases, but little is known about how concentric layers of muscle cells and the outer adventitial layer are assembled and patterned around endothelial tubes. Using histochemical, clonal, and genetic analysis in mice, here we show that the pulmonary artery wall is constructed radially, from the inside out, by two separate but coordinated processes. One is sequential induction of successive cell layers from surrounding mesenchyme. The other is controlled invasion of outer layers by inner layer cells through developmentally regulated cell reorientation and radial migration. We propose that a radial signal gradient controls these processes and provide evidence that PDGF-B and at least one other signal contribute. Modulation of such radial signaling pathways may underlie vessel-specific differences and pathological changes in arterial wall size and structure.


Assuntos
Artéria Pulmonar/fisiologia , Artéria Radial/fisiologia , Transdução de Sinais , Animais , Divisão Celular , Pulmão/citologia , Mesoderma/citologia , Camundongos , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-sis/metabolismo , Artéria Pulmonar/crescimento & desenvolvimento , Artéria Pulmonar/metabolismo , Artéria Radial/metabolismo
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