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1.
BMC Biol ; 22(1): 106, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715001

RESUMO

BACKGROUND: The significance of A-to-I RNA editing in nervous system development is widely recognized; however, its influence on retina development remains to be thoroughly understood. RESULTS: In this study, we performed RNA sequencing and ribosome profiling experiments on developing mouse retinas to characterize the temporal landscape of A-to-I editing. Our findings revealed temporal changes in A-to-I editing, with distinct editing patterns observed across different developmental stages. Further analysis showed the interplay between A-to-I editing and alternative splicing, with A-to-I editing influencing splicing efficiency and the quantity of splicing events. A-to-I editing held the potential to enhance translation diversity, but this came at the expense of reduced translational efficiency. When coupled with splicing, it could produce a coordinated effect on gene translation. CONCLUSIONS: Overall, this study presents a temporally resolved atlas of A-to-I editing, connecting its changes with the impact on alternative splicing and gene translation in retina development.


Assuntos
Biossíntese de Proteínas , Edição de RNA , Retina , Animais , Camundongos , Retina/metabolismo , Retina/embriologia , Processamento Alternativo , Inosina/metabolismo , Inosina/genética , Adenosina/metabolismo
2.
J Neuroinflammation ; 21(1): 118, 2024 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-38715090

RESUMO

Maternal inflammation during gestation is associated with a later diagnosis of neurodevelopmental disorders including autism spectrum disorder (ASD). However, the specific impact of maternal immune activation (MIA) on placental and fetal brain development remains insufficiently understood. This study aimed to investigate the effects of MIA by analyzing placental and brain tissues obtained from the offspring of pregnant C57BL/6 dams exposed to polyinosinic: polycytidylic acid (poly I: C) on embryonic day 12.5. Cytokine and mRNA content in the placenta and brain tissues were assessed using multiplex cytokine assays and bulk-RNA sequencing on embryonic day 17.5. In the placenta, male MIA offspring exhibited higher levels of GM-CSF, IL-6, TNFα, and LT-α, but there were no differences in female MIA offspring. Furthermore, differentially expressed genes (DEG) in the placental tissues of MIA offspring were found to be enriched in processes related to synaptic vesicles and neuronal development. Placental mRNA from male and female MIA offspring were both enriched in synaptic and neuronal development terms, whereas females were also enriched for terms related to excitatory and inhibitory signaling. In the fetal brain of MIA offspring, increased levels of IL-28B and IL-25 were observed with male MIA offspring and increased levels of LT-α were observed in the female offspring. Notably, we identified few stable MIA fetal brain DEG, with no male specific difference whereas females had DEG related to immune cytokine signaling. Overall, these findings support the hypothesis that MIA contributes to the sex- specific abnormalities observed in ASD, possibly through altered neuron developed from exposure to inflammatory cytokines. Future research should aim to investigate how interactions between the placenta and fetal brain contribute to altered neuronal development in the context of MIA.


Assuntos
Encéfalo , Citocinas , Camundongos Endogâmicos C57BL , Transtornos do Neurodesenvolvimento , Placenta , Efeitos Tardios da Exposição Pré-Natal , Caracteres Sexuais , Feminino , Animais , Gravidez , Masculino , Citocinas/metabolismo , Citocinas/genética , Camundongos , Encéfalo/metabolismo , Encéfalo/imunologia , Encéfalo/embriologia , Placenta/metabolismo , Placenta/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Transtornos do Neurodesenvolvimento/genética , Transtornos do Neurodesenvolvimento/imunologia , Transtornos do Neurodesenvolvimento/metabolismo , Poli I-C/toxicidade , Transcriptoma , Modelos Animais de Doenças , Feto/metabolismo
3.
Genesis ; 62(3): e23602, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38721990

RESUMO

Cilia play a key role in the regulation of signaling pathways required for embryonic development, including the proper formation of the neural tube, the precursor to the brain and spinal cord. Forward genetic screens were used to generate mouse lines that display neural tube defects (NTD) and secondary phenotypes useful in interrogating function. We describe here the L3P mutant line that displays phenotypes of disrupted Sonic hedgehog signaling and affects the initiation of cilia formation. A point mutation was mapped in the L3P line to the gene Rsg1, which encodes a GTPase-like protein. The mutation lies within the GTP-binding pocket and disrupts the highly conserved G1 domain. The mutant protein and other centrosomal and IFT proteins still localize appropriately to the basal body of cilia, suggesting that RSG1 GTPase activity is not required for basal body maturation but is needed for a downstream step in axonemal elongation.


Assuntos
Cílios , Defeitos do Tubo Neural , Tubo Neural , Animais , Cílios/metabolismo , Cílios/genética , Camundongos , Tubo Neural/metabolismo , Tubo Neural/embriologia , Defeitos do Tubo Neural/genética , Defeitos do Tubo Neural/metabolismo , Proteínas Hedgehog/metabolismo , Proteínas Hedgehog/genética , Transdução de Sinais , Mutação Puntual
4.
Curr Top Dev Biol ; 159: 168-231, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729676

RESUMO

The development of the vertebrate spinal cord involves the formation of the neural tube and the generation of multiple distinct cell types. The process starts during gastrulation, combining axial elongation with specification of neural cells and the formation of the neuroepithelium. Tissue movements produce the neural tube which is then exposed to signals that provide patterning information to neural progenitors. The intracellular response to these signals, via a gene regulatory network, governs the spatial and temporal differentiation of progenitors into specific cell types, facilitating the assembly of functional neuronal circuits. The interplay between the gene regulatory network, cell movement, and tissue mechanics generates the conserved neural tube pattern observed across species. In this review we offer an overview of the molecular and cellular processes governing the formation and patterning of the neural tube, highlighting how the remarkable complexity and precision of vertebrate nervous system arises. We argue that a multidisciplinary and multiscale understanding of the neural tube development, paired with the study of species-specific strategies, will be crucial to tackle the open questions.


Assuntos
Padronização Corporal , Regulação da Expressão Gênica no Desenvolvimento , Tubo Neural , Transdução de Sinais , Tubo Neural/embriologia , Tubo Neural/metabolismo , Tubo Neural/citologia , Animais , Padronização Corporal/genética , Humanos , Redes Reguladoras de Genes , Medula Espinal/embriologia , Medula Espinal/citologia , Medula Espinal/metabolismo , Diferenciação Celular , Movimento Celular
5.
Curr Top Dev Biol ; 159: 132-167, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729675

RESUMO

The primary senses-touch, taste, sight, smell, and hearing-connect animals with their environments and with one another. Aside from the eyes, the primary sense organs of vertebrates and the peripheral sensory pathways that relay their inputs arise from two transient stem cell populations: the neural crest and the cranial placodes. In this chapter we consider the senses from historical and cultural perspectives, and discuss the senses as biological faculties. We begin with the embryonic origin of the neural crest and cranial placodes from within the neural plate border of the ectodermal germ layer. Then, we describe the major chemical (i.e. olfactory and gustatory) and mechanical (i.e. vestibulo-auditory and somatosensory) senses, with an emphasis on the developmental interactions between neural crest and cranial placodes that shape their structures and functions.


Assuntos
Crista Neural , Animais , Crista Neural/citologia , Crista Neural/embriologia , Crista Neural/fisiologia , Humanos , Sensação/fisiologia , Órgãos dos Sentidos/embriologia , Órgãos dos Sentidos/fisiologia , Órgãos dos Sentidos/citologia , Vertebrados/embriologia , Vertebrados/fisiologia
6.
Curr Top Dev Biol ; 159: 232-271, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729677

RESUMO

The anterior-to-posterior (head-to-tail) body axis is extraordinarily diverse among vertebrates but conserved within species. Body axis development requires a population of axial progenitors that resides at the posterior of the embryo to sustain elongation and is then eliminated once axis extension is complete. These progenitors occupy distinct domains in the posterior (tail-end) of the embryo and contribute to various lineages along the body axis. The subset of axial progenitors with neuromesodermal competency will generate both the neural tube (the precursor of the spinal cord), and the trunk and tail somites (producing the musculoskeleton) during embryo development. These axial progenitors are called Neuromesodermal Competent cells (NMCs) and Neuromesodermal Progenitors (NMPs). NMCs/NMPs have recently attracted interest beyond the field of developmental biology due to their clinical potential. In the mouse, the maintenance of neuromesodermal competency relies on a fine balance between a trio of known signals: Wnt/ß-catenin, FGF signalling activity and suppression of retinoic acid signalling. These signals regulate the relative expression levels of the mesodermal transcription factor Brachyury and the neural transcription factor Sox2, permitting the maintenance of progenitor identity when co-expressed, and either mesoderm or neural lineage commitment when the balance is tilted towards either Brachyury or Sox2, respectively. Despite important advances in understanding key genes and cellular behaviours involved in these fate decisions, how the balance between mesodermal and neural fates is achieved remains largely unknown. In this chapter, we provide an overview of signalling and gene regulatory networks in NMCs/NMPs. We discuss mutant phenotypes associated with axial defects, hinting at the potential significant role of lesser studied proteins in the maintenance and differentiation of the progenitors that fuel axial elongation.


Assuntos
Padronização Corporal , Mesoderma , Animais , Padronização Corporal/genética , Mesoderma/metabolismo , Mesoderma/citologia , Mesoderma/embriologia , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Transdução de Sinais , Proteínas com Domínio T/metabolismo , Proteínas com Domínio T/genética , Diferenciação Celular , Cabeça/embriologia
7.
Curr Top Dev Biol ; 159: 1-27, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729674

RESUMO

The diversity of vertebrate body plans is dizzying, yet stunning for the many things they have in common. Vertebrates have inhabited virtually every part of the earth from its coldest to warmest climates. They locomote by swimming, flying, walking, slithering, or climbing, or combinations of these behaviors. And they exist in many different sizes, from the smallest of frogs, fish and lizards to giraffes, elephants, and blue whales. Despite these differences, vertebrates follow a remarkably similar blueprint for the establishment of their body plan. Within the relatively small amount of time required to complete gastrulation, the process through which the three germ layers, ectoderm, mesoderm, and endoderm are created, the embryo also generates its body axis and is simultaneously patterned. For the length of this axis, the genes that distinguish the neck from the rib cage or the trunk from the sacrum are the Hox genes. In vertebrates, there was evolutionary pressure to maintain this set of genes in the organism. Over the past decades, much has been learned regarding the regulatory mechanisms that ensure the appropriate expression of these genes along the main body axes. Genetic functions continue to be explored though much has been learned. Much less has been discerned on the identity of co-factors used by Hox proteins for the specificity of transcriptional regulation or what downstream targets and pathways are critical for patterning events, though there are notable exceptions. Current work in the field is demonstrating that Hox genes continue to function in many organs long after directing early patterning events. It is hopeful continued research will shed light on remaining questions regarding mechanisms used by this important and conserved set of transcriptional regulators.


Assuntos
Padronização Corporal , Regulação da Expressão Gênica no Desenvolvimento , Genes Homeobox , Vertebrados , Animais , Padronização Corporal/genética , Vertebrados/genética , Vertebrados/embriologia , Genes Homeobox/genética
8.
Curr Top Dev Biol ; 159: 344-370, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729681

RESUMO

The development of the vascular system is crucial in supporting the growth and health of all other organs in the body, and vascular system dysfunction is the major cause of human morbidity and mortality. This chapter discusses three successive processes that govern vascular system development, starting with the differentiation of the primitive vascular system in early embryonic development, followed by its remodeling into a functional circulatory system composed of arteries and veins, and its final maturation and acquisition of an organ specific semi-permeable barrier that controls nutrient uptake into tissues and hence controls organ physiology. Along these steps, endothelial cells forming the inner lining of all blood vessels acquire extensive heterogeneity in terms of gene expression patterns and function, that we are only beginning to understand. These advances contribute to overall knowledge of vascular biology and are predicted to unlock the unprecedented therapeutic potential of the endothelium as an avenue for treatment of diseases associated with dysfunctional vasculature.


Assuntos
Remodelação Vascular , Humanos , Animais , Vasos Sanguíneos/crescimento & desenvolvimento , Vasos Sanguíneos/metabolismo , Vasos Sanguíneos/embriologia , Neovascularização Fisiológica , Células Endoteliais/citologia , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Diferenciação Celular , Desenvolvimento Embrionário , Endotélio Vascular/citologia
9.
Curr Top Dev Biol ; 159: 372-405, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729682

RESUMO

The Segmentation Clock is a tissue-level patterning system that enables the segmentation of the vertebral column precursors into transient multicellular blocks called somites. This patterning system comprises a set of elements that are essential for correct segmentation. Under the so-called "Clock and Wavefront" model, the system consists of two elements, a genetic oscillator that manifests itself as traveling waves of gene expression, and a regressing wavefront that transforms the temporally periodic signal encoded in the oscillations into a permanent spatially periodic pattern of somite boundaries. Over the last twenty years, every new discovery about the Segmentation Clock has been tightly linked to the nomenclature of the "Clock and Wavefront" model. This constrained allocation of discoveries into these two elements has generated long-standing debates in the field as what defines molecularly the wavefront and how and where the interaction between the two elements establishes the future somite boundaries. In this review, we propose an expansion of the "Clock and Wavefront" model into three elements, "Clock", "Wavefront" and signaling gradients. We first provide a detailed description of the components and regulatory mechanisms of each element, and we then examine how the spatiotemporal integration of the three elements leads to the establishment of the presumptive somite boundaries. To be as exhaustive as possible, we focus on the Segmentation Clock in zebrafish. Furthermore, we show how this three-element expansion of the model provides a better understanding of the somite formation process and we emphasize where our current understanding of this patterning system remains obscure.


Assuntos
Padronização Corporal , Regulação da Expressão Gênica no Desenvolvimento , Mesoderma , Somitos , Animais , Padronização Corporal/genética , Somitos/embriologia , Somitos/metabolismo , Mesoderma/embriologia , Mesoderma/metabolismo , Mesoderma/citologia , Peixe-Zebra/embriologia , Peixe-Zebra/genética , Transdução de Sinais , Relógios Biológicos/genética
10.
Curr Top Dev Biol ; 159: 272-308, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729678

RESUMO

Although vertebrates display a large variety of forms and sizes, the mechanisms controlling the layout of the basic body plan are substantially conserved throughout the clade. Following gastrulation, head, trunk, and tail are sequentially generated through the continuous addition of tissue at the caudal embryonic end. Development of each of these major embryonic regions is regulated by a distinct genetic network. The transitions from head-to-trunk and from trunk-to-tail development thus involve major changes in regulatory mechanisms, requiring proper coordination to guarantee smooth progression of embryonic development. In this review, we will discuss the key cellular and embryological events associated with those transitions giving particular attention to their regulation, aiming to provide a cohesive outlook of this important component of vertebrate development.


Assuntos
Padronização Corporal , Regulação da Expressão Gênica no Desenvolvimento , Animais , Humanos , Desenvolvimento Embrionário , Gastrulação , Vertebrados/embriologia
11.
Curr Top Dev Biol ; 159: 30-58, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729679

RESUMO

Morphogenesis from cells to tissue gives rise to the complex architectures that make our organs. How cells and their dynamic behavior are translated into functional spatial patterns is only starting to be understood. Recent advances in quantitative imaging revealed that, although highly heterogeneous, cellular behaviors make reproducible tissue patterns. Emerging evidence suggests that mechanisms of cellular coordination, intrinsic variability and plasticity are critical for robust pattern formation. While pattern development shows a high level of fidelity, tissue organization has undergone drastic changes throughout the course of evolution. In addition, alterations in cell behavior, if unregulated, can cause developmental malformations that disrupt function. Therefore, comparative studies of different species and of disease models offer a powerful approach for understanding how novel spatial configurations arise from variations in cell behavior and the fundamentals of successful pattern formation. In this chapter, I dive into the development of the vertebrate nervous system to explore efforts to dissect pattern formation beyond molecules, the emerging core principles and open questions.


Assuntos
Sistema Nervoso , Vertebrados , Animais , Vertebrados/fisiologia , Vertebrados/embriologia , Sistema Nervoso/crescimento & desenvolvimento , Sistema Nervoso/embriologia , Padronização Corporal , Humanos , Morfogênese
12.
Curr Top Dev Biol ; 159: 310-342, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38729680

RESUMO

External bilateral symmetry is a prevalent feature in vertebrates, which emerges during early embryonic development. To begin with, vertebrate embryos are largely radially symmetric before transitioning to bilaterally symmetry, after which, morphogenesis of various bilateral tissues (e.g somites, otic vesicle, limb bud), and structures (e.g palate, jaw) ensue. While a significant amount of work has probed the mechanisms behind symmetry breaking in the left-right axis leading to asymmetric positioning of internal organs, little is known about how bilateral tissues emerge at the same time with the same shape and size and at the same position on the two sides of the embryo. By discussing emergence of symmetry in many bilateral tissues and structures across vertebrate model systems, we highlight that understanding symmetry establishment is largely an open field, which will provide deep insights into fundamental problems in developmental biology for decades to come.


Assuntos
Padronização Corporal , Vertebrados , Animais , Vertebrados/embriologia , Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Morfogênese , Somitos/embriologia
13.
Brief Bioinform ; 25(3)2024 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-38739758

RESUMO

The complicated process of neuronal development is initiated early in life, with the genetic mechanisms governing this process yet to be fully elucidated. Single-cell RNA sequencing (scRNA-seq) is a potent instrument for pinpointing biomarkers that exhibit differential expression across various cell types and developmental stages. By employing scRNA-seq on human embryonic stem cells, we aim to identify differentially expressed genes (DEGs) crucial for early-stage neuronal development. Our focus extends beyond simply identifying DEGs. We strive to investigate the functional roles of these genes through enrichment analysis and construct gene regulatory networks to understand their interactions. Ultimately, this comprehensive approach aspires to illuminate the molecular mechanisms and transcriptional dynamics governing early human brain development. By uncovering potential links between these DEGs and intelligence, mental disorders, and neurodevelopmental disorders, we hope to shed light on human neurological health and disease. In this study, we have used scRNA-seq to identify DEGs involved in early-stage neuronal development in hESCs. The scRNA-seq data, collected on days 26 (D26) and 54 (D54), of the in vitro differentiation of hESCs to neurons were analyzed. Our analysis identified 539 DEGs between D26 and D54. Functional enrichment of those DEG biomarkers indicated that the up-regulated DEGs participated in neurogenesis, while the down-regulated DEGs were linked to synapse regulation. The Reactome pathway analysis revealed that down-regulated DEGs were involved in the interactions between proteins located in synapse pathways. We also discovered interactions between DEGs and miRNA, transcriptional factors (TFs) and DEGs, and between TF and miRNA. Our study identified 20 significant transcription factors, shedding light on early brain development genetics. The identified DEGs and gene regulatory networks are valuable resources for future research into human brain development and neurodevelopmental disorders.


Assuntos
Biomarcadores , Encéfalo , Redes Reguladoras de Genes , Células-Tronco Embrionárias Humanas , Análise de Célula Única , Humanos , Análise de Célula Única/métodos , Células-Tronco Embrionárias Humanas/metabolismo , Células-Tronco Embrionárias Humanas/citologia , Encéfalo/metabolismo , Encéfalo/embriologia , Encéfalo/citologia , Biomarcadores/metabolismo , Neurônios/metabolismo , Neurônios/citologia , Diferenciação Celular/genética , RNA-Seq , Neurogênese/genética , Regulação da Expressão Gênica no Desenvolvimento , Perfilação da Expressão Gênica , Análise de Sequência de RNA/métodos , Análise da Expressão Gênica de Célula Única
14.
Birth Defects Res ; 116(5): e2351, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38766695

RESUMO

BACKGROUND: Pathogenic copy number variants (pCNVs) are associated with fetal ultrasound anomalies, which can be efficiently identified through chromosomal microarray analysis (CMA). The primary objective of the present study was to enhance understanding of the genotype-phenotype correlation in fetuses exhibiting absent or hypoplastic nasal bones using CMA. METHODS: Enrolled in the present study were 94 cases of fetuses with absent/hypoplastic nasal bone, which were divided into an isolated absent/hypoplastic nasal bone group (n = 49) and a non-isolated group (n = 45). All pregnant women enrolled in the study underwent karyotype analysis and CMA to assess chromosomal abnormalities in the fetuses. RESULTS: Karyotype analysis and CMA detection were successfully performed in all cases. The results of karyotype and CMA indicate the presence of 11 cases of chromosome aneuploidy, with trisomy 21 being the most prevalent among them. A small supernumerary marker chromosome (sSMC) detected by karyotype analysis was further interpreted as a pCNV by CMA. Additionally, CMA detection elicited three cases of pCNVs, despite normal findings in their karyotype analysis results. Among them, one case of Roche translocation was identified to be a UPD in chromosome 15 with a low proportion of trisomy 15. Further, a significant difference in the detection rate of pCNVs was observed between non-isolated and isolated absent/hypoplastic nasal bone (24.44% vs. 8.16%, p < .05). CONCLUSION: The present study enhances the utility of CMA in diagnosing the etiology of absent or hypoplastic nasal bone in fetuses. Further, isolated cases of absent or hypoplastic nasal bone strongly suggest the presence of chromosomal abnormalities, necessitating genetic evaluation through CMA.


Assuntos
Variações do Número de Cópias de DNA , Cariotipagem , Análise em Microsséries , Osso Nasal , Segundo Trimestre da Gravidez , Diagnóstico Pré-Natal , Humanos , Feminino , Osso Nasal/diagnóstico por imagem , Osso Nasal/anormalidades , Gravidez , Análise em Microsséries/métodos , Adulto , Diagnóstico Pré-Natal/métodos , Variações do Número de Cópias de DNA/genética , Cariotipagem/métodos , Feto , Aberrações Cromossômicas/embriologia , Ultrassonografia Pré-Natal/métodos , Estudos de Associação Genética/métodos
15.
Cell Biol Toxicol ; 40(1): 34, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38769159

RESUMO

Anorectal malformation (ARM) is a prevalent early pregnancy digestive tract anomaly. The intricate anatomy of the embryonic cloaca region makes it challenging for traditional high-throughput sequencing methods to capture location-specific information. Spatial transcriptomics was used to sequence libraries of frozen sections from embryonic rats at gestational days (GD) 14 to 16, covering both normal and ARM cases. Bioinformatics analyses and predictions were performed using methods such as WGCNA, GSEA, and PROGENy. Immunofluorescence staining was used to verify gene expression levels. Gene expression data was obtained with anatomical annotations of clusters, focusing on the cloaca region's location-specific traits. WGCNA revealed gene modules linked to normal and ARM cloacal anatomy development, with cooperation between modules on GD14 and GD15. Differential gene expression profiles and functional enrichment were presented. Notably, protein levels of Pcsk9, Hmgb2, and Sod1 were found to be downregulated in the GD15 ARM hindgut. The PROGENy algorithm predicted the activity and interplay of common signaling pathways in embryonic sections, highlighting their synergistic and complementary effects. A competing endogenous RNA (ceRNA) regulatory network was constructed from whole transcriptome data. Spatial transcriptomics provided location-specific cloaca region gene expression. Diverse bioinformatics analyses deepened our understanding of ARM's molecular interactions, guiding future research and providing insights into gene regulation in ARM development.


Assuntos
Malformações Anorretais , Redes Reguladoras de Genes , Transdução de Sinais , Transcriptoma , Animais , Malformações Anorretais/genética , Malformações Anorretais/metabolismo , Malformações Anorretais/embriologia , Transdução de Sinais/genética , Transcriptoma/genética , Ratos , Feminino , Regulação da Expressão Gênica no Desenvolvimento , Gravidez , Embrião de Mamíferos/metabolismo , Perfilação da Expressão Gênica/métodos , Biologia Computacional/métodos , Ratos Sprague-Dawley , Cloaca/embriologia , Cloaca/metabolismo
16.
Int J Mol Sci ; 25(9)2024 May 06.
Artigo em Inglês | MEDLINE | ID: mdl-38732272

RESUMO

Lung branching morphogenesis relies on intricate epithelial-mesenchymal interactions and signaling networks. Still, the interplay between signaling and energy metabolism in shaping embryonic lung development remains unexplored. Retinoic acid (RA) signaling influences lung proximal-distal patterning and branching morphogenesis, but its role as a metabolic modulator is unknown. Hence, this study investigates how RA signaling affects the metabolic profile of lung branching. We performed ex vivo lung explant culture of embryonic chicken lungs treated with DMSO, 1 µM RA, or 10 µM BMS493. Extracellular metabolite consumption/production was evaluated by using 1H-NMR spectroscopy. Mitochondrial respiration and biogenesis were also analyzed. Proliferation was assessed using an EdU-based assay. The expression of crucial metabolic/signaling components was examined through Western blot, qPCR, and in situ hybridization. RA signaling stimulation redirects glucose towards pyruvate and succinate production rather than to alanine or lactate. Inhibition of RA signaling reduces lung branching, resulting in a cystic-like phenotype while promoting mitochondrial function. Here, RA signaling emerges as a regulator of tissue proliferation and lactate dehydrogenase expression. Furthermore, RA governs fatty acid metabolism through an AMPK-dependent mechanism. These findings underscore RA's pivotal role in shaping lung metabolism during branching morphogenesis, contributing to our understanding of lung development and cystic-related lung disorders.


Assuntos
Metabolismo Energético , Pulmão , Morfogênese , Transdução de Sinais , Tretinoína , Animais , Tretinoína/metabolismo , Tretinoína/farmacologia , Pulmão/metabolismo , Pulmão/efeitos dos fármacos , Pulmão/embriologia , Metabolismo Energético/efeitos dos fármacos , Morfogênese/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Embrião de Galinha , Proliferação de Células/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/efeitos dos fármacos , Galinhas
17.
Development ; 151(9)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38738653

RESUMO

During alveologenesis, multiple mesenchymal cell types play crucial roles in maximising the lung surface area. In their study, David Ornitz and colleagues define the repertoire of lung fibroblasts, with a particular focus on alveolar myofibroblasts. To know more about their work, we spoke to the first author, Yongjun Yin, and the corresponding author, David Ornitz, Alumni Endowed Professor at the Department of Developmental Biology, Washington University School of Medicine, St. Louis.


Assuntos
Biologia do Desenvolvimento , Humanos , História do Século XXI , Biologia do Desenvolvimento/história , História do Século XX , Pulmão/embriologia , Pulmão/metabolismo , Pulmão/citologia , Animais
18.
Development ; 151(9)2024 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-38727565

RESUMO

Proper embryonic development depends on the timely progression of a genetic program. One of the key mechanisms for achieving precise control of developmental timing is to use gene expression oscillations. In this Review, we examine how gene expression oscillations encode temporal information during vertebrate embryonic development by discussing the gene expression oscillations occurring during somitogenesis, neurogenesis, myogenesis and pancreas development. These oscillations play important but varied physiological functions in different contexts. Oscillations control the period of somite formation during somitogenesis, whereas they regulate the proliferation-to-differentiation switch of stem cells and progenitor cells during neurogenesis, myogenesis and pancreas development. We describe the similarities and differences of the expression pattern in space (i.e. whether oscillations are synchronous or asynchronous across neighboring cells) and in time (i.e. different time scales) of mammalian Hes/zebrafish Her genes and their targets in different tissues. We further summarize experimental evidence for the functional role of their oscillations. Finally, we discuss the outstanding questions for future research.


Assuntos
Desenvolvimento Embrionário , Regulação da Expressão Gênica no Desenvolvimento , Somitos , Animais , Desenvolvimento Embrionário/genética , Humanos , Somitos/metabolismo , Somitos/embriologia , Desenvolvimento Muscular/genética , Neurogênese/genética , Neurogênese/fisiologia , Pâncreas/embriologia , Pâncreas/metabolismo , Diferenciação Celular/genética
19.
PLoS One ; 19(5): e0301082, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38722977

RESUMO

Branching morphogenesis is a complex process shared by many organs including the lungs, kidney, prostate, as well as several exocrine organs including the salivary, mammary and lacrimal glands. This critical developmental program ensures the expansion of an organ's surface area thereby maximizing processes of cellular secretion or absorption. It is guided by reciprocal signaling from the epithelial and mesenchymal cells. While signaling pathways driving salivary gland branching morphogenesis have been relatively well-studied, our understanding of the underlying transcriptional regulatory mechanisms directing this program, is limited. Here, we performed in vivo and ex vivo studies of the embryonic mouse submandibular gland to determine the function of the transcription factor ΔNp63, in directing branching morphogenesis. Our studies show that loss of ΔNp63 results in alterations in the differentiation program of the ductal cells which is accompanied by a dramatic reduction in branching morphogenesis that is mediated by dysregulation of WNT signaling. We show that ΔNp63 modulates WNT signaling to promote branching morphogenesis by directly regulating Sfrp1 expression. Collectively, our findings have revealed a novel role for ΔNp63 in the regulation of this critical process and offers a better understanding of the transcriptional networks involved in branching morphogenesis.


Assuntos
Regulação da Expressão Gênica no Desenvolvimento , Proteínas de Membrana , Morfogênese , Animais , Camundongos , Morfogênese/genética , Proteínas de Membrana/metabolismo , Proteínas de Membrana/genética , Peptídeos e Proteínas de Sinalização Intercelular/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/genética , Glândulas Salivares/metabolismo , Glândulas Salivares/embriologia , Via de Sinalização Wnt , Glândula Submandibular/metabolismo , Glândula Submandibular/embriologia , Transativadores/metabolismo , Transativadores/genética , Diferenciação Celular
20.
Development ; 151(10)2024 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-38738602

RESUMO

Visual circuit development is characterized by subdivision of neuropils into layers that house distinct sets of synaptic connections. We find that, in the Drosophila medulla, this layered organization depends on the axon guidance regulator Plexin A. In Plexin A null mutants, synaptic layers of the medulla neuropil and arborizations of individual neurons are wider and less distinct than in controls. Analysis of semaphorin function indicates that Semaphorin 1a, acting in a subset of medulla neurons, is the primary partner for Plexin A in medulla lamination. Removal of the cytoplasmic domain of endogenous Plexin A has little effect on the formation of medulla layers; however, both null and cytoplasmic domain deletion mutations of Plexin A result in an altered overall shape of the medulla neuropil. These data suggest that Plexin A acts as a receptor to mediate morphogenesis of the medulla neuropil, and as a ligand for Semaphorin 1a to subdivide it into layers. Its two independent functions illustrate how a few guidance molecules can organize complex brain structures by each playing multiple roles.


Assuntos
Proteínas de Drosophila , Morfogênese , Proteínas do Tecido Nervoso , Neurópilo , Lobo Óptico de Animais não Mamíferos , Receptores de Superfície Celular , Semaforinas , Animais , Proteínas de Drosophila/metabolismo , Proteínas de Drosophila/genética , Semaforinas/metabolismo , Semaforinas/genética , Proteínas do Tecido Nervoso/metabolismo , Proteínas do Tecido Nervoso/genética , Morfogênese/genética , Neurópilo/metabolismo , Lobo Óptico de Animais não Mamíferos/metabolismo , Lobo Óptico de Animais não Mamíferos/embriologia , Receptores de Superfície Celular/metabolismo , Receptores de Superfície Celular/genética , Drosophila melanogaster/metabolismo , Drosophila melanogaster/genética , Drosophila melanogaster/embriologia , Neurônios/metabolismo , Drosophila/metabolismo , Drosophila/embriologia , Mutação/genética
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