scholarly journals Multilevel regulation of the glass locus during Drosophila eye development

2019 ◽  
Author(s):  
Cornelia Fritsch ◽  
F. Javier Bernardo-Garcia ◽  
Tim-Henning Humberg ◽  
Sara Miellet ◽  
Silvia Almeida ◽  
...  
Keyword(s):  
Cell Fate ◽  
Molecular Mechanisms ◽  
Eye Development ◽  
Fruit Fly ◽  
Protein Isoforms ◽  
Critical Feature ◽  
Reading Frame ◽  
Cis Acting ◽  
Temporal Gene Expression ◽  
And Function

ABSTRACTDevelopment of eye tissue is initiated by a conserved set of transcripton factors termed retinal determination network (RDN). In the fruit fly Drosophila melanogaster, the zinc-finger transcription factor Glass acts directly downstream of the RDN to control idendity of photoreceptor as well as non-photoreceptors cells. Tight control of spatial and temporal gene expression is a critical feature during development, cell-fate determination as well as maintainance of differentiated tissues. The molecular mechanisms that control expression of glass, however remain largely unknown. We here identify complex regulatory mechanisms controlling expression of the glass locus. All information to recapitulate glass expression are contained in a compact 5.2 kb cis-acting genomic element by combining different cell-type specific and general enhancers with repressor elements. Moreover, the immature RNA of the locus contains an alterantive small open reading frame (smORF) upstream of the actual glass translation start, resulting in a small peptide instead of the three possible glass protein isoforms. CRISPR/Cas9-based mutagenesis shows that the smORF is not required for the formation of functioning photoreceptors, but to attenuate effects of glass misexpression. Furthermore, editing the genome to generate glass loci eliminating either one or two isoforms shows that only one of the three proteins is critical for formation of functioning photoreceptors, while removing the two other isoforms did not cause defects in developmental or photoreceptor function. Our results show that eye development and function is surprisingly robust and appears buffered to targeted manipulations of critical features of the glass transcript, suggesting a strong selection pressure to allow the formation of a functioning eye.

scholarly journals Mechanosensation and Mechanotransduction by Lymphatic Endothelial Cells Act as Important Regulators of Lymphatic Development and Function

2021 ◽  
Vol 22 (8) ◽  
pp. 3955
Author(s):  
László Bálint ◽  
Zoltán Jakus
Keyword(s):  
Endothelial Cells ◽  
Endothelial Cell ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Mechanical Forces ◽  
Lymphatic Endothelial Cells ◽  
Lymphatic Development ◽  
And Function ◽  
The Impact

Our understanding of the function and development of the lymphatic system is expanding rapidly due to the identification of specific molecular markers and the availability of novel genetic approaches. In connection, it has been demonstrated that mechanical forces contribute to the endothelial cell fate commitment and play a critical role in influencing lymphatic endothelial cell shape and alignment by promoting sprouting, development, maturation of the lymphatic network, and coordinating lymphatic valve morphogenesis and the stabilization of lymphatic valves. However, the mechanosignaling and mechanotransduction pathways involved in these processes are poorly understood. Here, we provide an overview of the impact of mechanical forces on lymphatics and summarize the current understanding of the molecular mechanisms involved in the mechanosensation and mechanotransduction by lymphatic endothelial cells. We also discuss how these mechanosensitive pathways affect endothelial cell fate and regulate lymphatic development and function. A better understanding of these mechanisms may provide a deeper insight into the pathophysiology of various diseases associated with impaired lymphatic function, such as lymphedema and may eventually lead to the discovery of novel therapeutic targets for these conditions.

scholarly journals Molecular mechanisms behind mRNA localization in axons

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200177
Author(s):  
Benita Turner-Bridger ◽  
Cinzia Caterino ◽  
Jean-Michel Cioni
Keyword(s):  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Neuronal Development ◽  
Mrna Localization ◽  
Adaptive Responses ◽  
Cis Acting ◽  
Spatiotemporal Regulation ◽  
Mrna Content ◽  
Specific Mrnas ◽  
And Function

Messenger RNA (mRNA) localization allows spatiotemporal regulation of the proteome at the subcellular level. This is observed in the axons of neurons, where mRNA localization is involved in regulating neuronal development and function by orchestrating rapid adaptive responses to extracellular cues and the maintenance of axonal homeostasis through local translation. Here, we provide an overview of the key findings that have broadened our knowledge regarding how specific mRNAs are trafficked and localize to axons. In particular, we review transcriptomic studies investigating mRNA content in axons and the molecular principles underpinning how these mRNAs arrived there, including cis-acting mRNA sequences and trans-acting proteins playing a role. Further, we discuss evidence that links defective axonal mRNA localization and pathological outcomes.

scholarly journals Human Slug Is a Repressor That Localizes to Sites of Active Transcription

2000 ◽  
Vol 20 (14) ◽  
pp. 5087-5095 ◽  
Author(s):  
Kirugaval Hemavathy ◽  
Siradanahalli C. Guru ◽  
John Harris ◽  
J. Don Chen ◽  
Y. Tony Ip
Keyword(s):  
Dna Binding ◽  
Cell Fate ◽  
Histone Deacetylases ◽  
Molecular Mechanisms ◽  
Target Genes ◽  
Protein Localization ◽  
Zinc Fingers ◽  
Cell Movement ◽  
Left Right Asymmetry ◽  
And Function

ABSTRACT Snail/Slug family proteins have been identified in diverse species of both vertebrates and invertebrates. The proteins contain four to six zinc fingers and function as DNA-binding transcriptional regulators. Various members of the family have been demonstrated to regulate cell movement, neural cell fate, left-right asymmetry, cell cycle, and apoptosis. However, the molecular mechanisms of how these regulators function and the target genes involved are largely unknown. In this report, we demonstrate that human Slug (hSlug) is a repressor and modulates both activator-dependent and basal transcription. The repression depends on the C-terminal DNA-binding zinc fingers and on a separable repression domain located in the N terminus. This domain may recruit histone deacetylases to modify the chromatin and effect repression. Protein localization study demonstrates that hSlug is present in discrete foci in the nucleus. This subnuclear pattern does not colocalize with the PML foci or the coiled bodies. Instead, the hSlug foci overlap extensively with areas of the SC-35 staining, some of which have been suggested to be sites of active splicing or transcription. These results lead us to postulate that hSlug localizes to target promoters, where activation occurs, to repress basal and activator-mediated transcription.

scholarly journals Palytoxin: exploiting a novel skin tumor promoter to explore signal transduction and carcinogenesis

2007 ◽  
Vol 292 (1) ◽  
pp. C24-C32 ◽  
Author(s):  
Elizabeth V. Wattenberg
Keyword(s):  
Protein Kinase C ◽  
Protein Kinase ◽  
Cell Fate ◽  
Molecular Mechanisms ◽  
Mouse Skin ◽  
Tumor Promotion ◽  
Skin Tumor ◽  
Tumor Promoter ◽  
Kinase C ◽  
And Function

Palytoxin is a novel skin tumor promoter, which has been used to help probe the role of different types of signaling mechanisms in carcinogenesis. The multistage mouse skin model indicates that tumor promotion is an early, prolonged, and reversible phase of carcinogenesis. Understanding the molecular mechanisms underlying tumor promotion is therefore important for developing strategies to prevent and treat cancer. Naturally occurring tumor promoters that bind to specific cellular receptors have proven to be useful tools for investigating important biochemical events in multistage carcinogenesis. For example, the identification of protein kinase C as the receptor for the prototypical skin tumor promoter 12- O-tetradecanoylphorbol-13-acetate (TPA) (also called phorbol 12-myristate 13-acetate, PMA) provided key evidence that tumor promotion involves the aberrant modulation of signaling cascades that govern cell fate and function. The subsequent discovery that palytoxin, a marine toxin isolated from zoanthids (genus Palythoa), is a potent skin tumor promoter yet does not activate protein kinase C indicated that investigating palytoxin action could help reveal new aspects of tumor promotion. Interestingly, the putative receptor for palytoxin is the Na+,K+-ATPase. This review focuses on palytoxin-stimulated signaling and how palytoxin has been used to investigate alternate biochemical mechanisms by which important targets in carcinogenesis can be modulated.

No pun intended: future directions in invertebrate glial cell migration studies

2007 ◽  
Vol 3 (1) ◽  
pp. 45-54 ◽  
Author(s):  
Patrick Cafferty ◽  
Vanessa J. Auld
Keyword(s):  
Nervous System ◽  
Cell Migration ◽  
Glial Cell ◽  
Glial Cells ◽  
Molecular Mechanisms ◽  
System Development ◽  
Fruit Fly ◽  
Nervous System Development ◽  
Wide Range ◽  
And Function

AbstractGlial cells play a wide range of essential roles in both nervous system development and function and has been reviewed recently (Parker and Auld, 2006). Glia provide an insulating sheath, either form or direct the formation of the blood–brain barrier, contribute to ion and metabolite homeostasis and provide guidance cues. Glial function often depends on the ability of glial cells to migrate toward specific locations during nervous system development. Work in nervous system development in insects, in particular in the fruit fly Drosophila melanogaster and the tobacco hornworm Manduca sexta, has provided significant insight into the roles of glia, although the molecular mechanisms underlying glial cell migration are being determined only now. Indeed, many of the processes and mechanisms discovered in these simpler systems have direct parallels in the development of vertebrate nervous systems. In this review, we first examine the developmental contexts in which invertebrate glial cell migration has been observed, we next discuss the characterized molecules required for proper glial cell migration, and we finally discuss future goals to be addressed in the study of glial cell development.

scholarly journals MiR-155–regulated molecular network orchestrates cell fate in the innate and adaptive immune response to Mycobacterium tuberculosis

2016 ◽  
Vol 113 (41) ◽  
pp. E6172-E6181 ◽  
Author(s):  
Alissa C. Rothchild ◽  
James R. Sissons ◽  
Shahin Shafiani ◽  
Christopher Plaisier ◽  
Deborah Min ◽  
...  
Keyword(s):  
Immune Response ◽  
Mycobacterium Tuberculosis ◽  
Cell Survival ◽  
Cell Fate ◽  
Adaptive Immune Response ◽  
Sh2 Domain ◽  
Temporal Gene Expression ◽  
Adaptive Immune ◽  
Adaptive Immune Cells ◽  
And Function

The regulation of host–pathogen interactions during Mycobacterium tuberculosis (Mtb) infection remains unresolved. MicroRNAs (miRNAs) are important regulators of the immune system, and so we used a systems biology approach to construct an miRNA regulatory network activated in macrophages during Mtb infection. Our network comprises 77 putative miRNAs that are associated with temporal gene expression signatures in macrophages early after Mtb infection. In this study, we demonstrate a dual role for one of these regulators, miR-155. On the one hand, miR-155 maintains the survival of Mtb-infected macrophages, thereby providing a niche favoring bacterial replication; on the other hand, miR-155 promotes the survival and function of Mtb-specific T cells, enabling an effective adaptive immune response. MiR-155–induced cell survival is mediated through the SH2 domain-containing inositol 5-phosphatase 1 (SHIP1)/protein kinase B (Akt) pathway. Thus, dual regulation of the same cell survival pathway in innate and adaptive immune cells leads to vastly different outcomes with respect to bacterial containment.

scholarly journals Dysfunction of Torr causes a Harlequin-type ichthyosis-like phenotype in Drosophila melanogaster

2019 ◽  
Author(s):  
Y Wang ◽  
M Norum ◽  
K Oehl ◽  
Y Yang ◽  
R Zuber ◽  
...  
Keyword(s):  
Drosophila Melanogaster ◽  
Cuticular Hydrocarbons ◽  
Abc Transporter ◽  
Water Loss ◽  
Molecular Mechanisms ◽  
Fruit Fly ◽  
Skin Surface ◽  
Barrier Formation ◽  
Pore Canals ◽  
And Function

AbstractPrevention of desiccation is a constant challenge for terrestrial organisms. Land insects have an extracellular coat, the cuticle, that plays a major role in protection against exaggerated water loss. Here, we report that the ABC transporter Torr - a human ABCA12 paralog - contributes to the waterproof barrier function of the cuticle in the fruit fly Drosophila melanogaster. We show that the reduction or elimination of Torr function provokes rapid desiccation. Torr is also involved in defining the inward barrier against xenobiotics penetration. Consistently, the amounts of cuticular hydrocarbons that are involved in cuticle impermeability decrease markedly when Torr activity is reduced. GFP-tagged Torr localises to membrane nano-protrusions within the cuticle, likely pore canals. This suggests that Torr is mediating the transport of cuticular hydrocarbons (CHC) through the pore canals to the cuticle surface. The envelope, which is the outermost cuticle layer constituting the main barrier, is unaffected in torr mutant larvae. This contrasts with the function of Snu, another ABC transporter needed for the construction of the cuticular inward and outward barriers, that nevertheless is implicated in CHC deposition. Hence, Torr and Snu have overlapping and independent roles to establish cuticular resistance against transpiration and xenobiotic penetration. The torr deficient phenotype parallels the phenotype of Harlequin ichthyosis caused by mutations in the human abca12 gene. Thus, it seems that the cellular and molecular mechanisms of lipid barrier assembly in the skin are conserved in vertebrates in invertebrates.Author SummaryAs in humans, lipids on the surface of the skin of insects protect the organism against excessive water loss and penetration of potentially harmful substances. During evolution, a greasy surface was indeed an essential trait for adaptation to life outside a watery environment. Here, we show that the membrane-gate transporter Torr is needed for the deposition of barrier lipids on the skin surface in the fruit fly Drosophila melanogaster through extracellular nano-tubes, called pore canals. In principle, the involvement of Torr parallels the scenario in humans, where the membrane-gate transporter ABCA12 is implicated in the construction of the lipid-based stratum corneum of the skin. In both cases, mutations in the genes coding for the respective transporter cause rapid water-loss and are lethal soon after birth. We conclude that the interaction between the organism and the environment obviously implies an analogous mechanism of barrier formation and function in vertebrates and invertebrates.

scholarly journals Endothelial Mitogen-Activated Protein Kinase Kinase Kinase Kinase 4 Is Critical for Lymphatic Vascular Development and Function

2016 ◽  
Vol 36 (12) ◽  
pp. 1740-1749 ◽  
Author(s):  
Rachel J. Roth Flach ◽  
Chang-An Guo ◽  
Laura V. Danai ◽  
Joseph C. Yawe ◽  
Sharvari Gujja ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Protein Kinase ◽  
Cell Fate ◽  
Vascular Function ◽  
Molecular Mechanisms ◽  
Vascular Development ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
And Function ◽  
Protein Kinase Kinase

The molecular mechanisms underlying lymphatic vascular development and function are not well understood. Recent studies have suggested a role for endothelial cell (EC) mitogen-activated protein kinase kinase kinase kinase 4 (Map4k4) in developmental angiogenesis and atherosclerosis. Here, we show that constitutive loss of EC Map4k4 in mice causes postnatal lethality due to chylothorax, suggesting that Map4k4 is required for normal lymphatic vascular function. Mice constitutively lacking EC Map4k4 displayed dilated lymphatic capillaries, insufficient lymphatic valves, and impaired lymphatic flow; furthermore, primary ECs derived from these animals displayed enhanced proliferation compared with controls. Yeast 2-hybrid analyses identified the Ras GTPase-activating protein Rasa1, a known regulator of lymphatic development and lymphatic endothelial cell fate, as a direct interacting partner for Map4k4. Map4k4 silencing in ECs enhanced basal Ras and extracellular signal-regulated kinase (Erk) activities, and primary ECs lacking Map4k4 displayed enhanced lymphatic EC marker expression. Taken together, these results reveal that EC Map4k4 is critical for lymphatic vascular development by regulating EC quiescence and lymphatic EC fate.

scholarly journals Transcription Factors: The Fulcrum Between Cell Development and Carcinogenesis

2021 ◽  
Vol 11 ◽  
Author(s):  
Zeyaul Islam ◽  
Ameena Mohamed Ali ◽  
Adviti Naik ◽  
Mohamed Eldaw ◽  
Julie Decock ◽  
...  
Keyword(s):  
Transcription Factors ◽  
Cell Fate ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Molecular Mechanisms ◽  
Tumor Development ◽  
Treatment Resistance ◽  
Cell Development ◽  
Fate Decision ◽  
And Function

Higher eukaryotic development is a complex and tightly regulated process, whereby transcription factors (TFs) play a key role in controlling the gene regulatory networks. Dysregulation of these regulatory networks has also been associated with carcinogenesis. Transcription factors are key enablers of cancer stemness, which support the maintenance and function of cancer stem cells that are believed to act as seeds for cancer initiation, progression and metastasis, and treatment resistance. One key area of research is to understand how these factors interact and collaborate to define cellular fate during embryogenesis as well as during tumor development. This review focuses on understanding the role of TFs in cell development and cancer. The molecular mechanisms of cell fate decision are of key importance in efforts towards developing better protocols for directed differentiation of cells in research and medicine. We also discuss the dysregulation of TFs and their role in cancer progression and metastasis, exploring TF networks as direct or indirect targets for therapeutic intervention, as well as specific TFs’ potential as biomarkers for predicting and monitoring treatment responses.

scholarly journals Integrative genomic analysis of early neurogenesis reveals a temporal genetic program for differentiation and specification of preplate and Cajal-Retzius neurons

PLoS Genetics ◽  
2021 ◽  
Vol 17 (3) ◽  
pp. e1009355
Author(s):  
Jia Li ◽  
Lei Sun ◽  
Xue-Liang Peng ◽  
Xiao-Ming Yu ◽  
Shao-Jun Qi ◽  
...  
Keyword(s):  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Genomic Analysis ◽  
Sequencing Analysis ◽  
Temporal Gene Expression ◽  
Developing Neocortex ◽  
Early Neurogenesis ◽  
And Function

Neurogenesis in the developing neocortex begins with the generation of the preplate, which consists of early-born neurons including Cajal-Retzius (CR) cells and subplate neurons. Here, utilizing the Ebf2-EGFP transgenic mouse in which EGFP initially labels the preplate neurons then persists in CR cells, we reveal the dynamic transcriptome profiles of early neurogenesis and CR cell differentiation. Genome-wide RNA-seq and ChIP-seq analyses at multiple early neurogenic stages have revealed the temporal gene expression dynamics of early neurogenesis and distinct histone modification patterns in early differentiating neurons. We have identified a new set of coding genes and lncRNAs involved in early neuronal differentiation and validated with functional assays in vitro and in vivo. In addition, at E15.5 when Ebf2-EGFP+ cells are mostly CR neurons, single-cell sequencing analysis of purified Ebf2-EGFP+ cells uncovers molecular heterogeneities in CR neurons, but without apparent clustering of cells with distinct regional origins. Along a pseudotemporal trajectory these cells are classified into three different developing states, revealing genetic cascades from early generic neuronal differentiation to late fate specification during the establishment of CR neuron identity and function. Our findings shed light on the molecular mechanisms governing the early differentiation steps during cortical development, especially CR neuron differentiation.

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