Wnt signalling is known to generate cellular asymmetry via Wnt/planar cell polarity pathway (Wnt/PCP). Wnt/PCP acts locally (i) to orient membrane polarity and asymmetric establishment of intercellular junctions via conserved set of PCP proteins most specifically represented by Vangl and Prickle, and (ii) to asymmetrically rearrange cytoskeletal structures via downstream effectors of Dishevelled (Dvl). This process is best described on stable phenotypes of epithelial cells. Here, however, we review the activity of Wnt signalling in migratory cells which experience the extensive rearrangements of cytoskeleton and consequently dynamic asymmetry, making the localised effects of Wnt signalling easier to distinguish. Firstly, we focused on migration of neuronal axons, which allows to study how the pre-existent cellular asymmetry can influence Wnt signalling outcome. Then, we reviewed the role of Wnt signalling in models of mesenchymal migration including neural crest, melanoma, and breast cancer cells. Last, we collected evidence for local Wnt signalling in amoeboid cells, especially lymphocytes. As the outcome of this review, we identify blank spots in our current understanding of this topic, propose models that synthesise the current observations and allow formulation of testable hypotheses for the future research.
- MeSH
- crista neuralis MeSH
- epitelové buňky MeSH
- obratlovci MeSH
- polarita buněk * fyziologie MeSH
- signální dráha Wnt * fyziologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Satellite DNAs are present on every chromosome in the cell and are typically enriched in repetitive, heterochromatic parts of the human genome. Sex chromosomes represent a unique genomic and epigenetic context. In this review, we first report what is known about satellite DNA biology on human X and Y chromosomes, including repeat content and organization, as well as satellite variation in typical euploid individuals. Then, we review sex chromosome aneuploidies that are among the most common types of aneuploidies in the general population, and are better tolerated than autosomal aneuploidies. This is demonstrated also by the fact that aging is associated with the loss of the X, and especially the Y chromosome. In addition, supernumerary sex chromosomes enable us to study general processes in a cell, such as analyzing heterochromatin dosage (i.e. additional Barr bodies and long heterochromatin arrays on Yq) and their downstream consequences. Finally, genomic and epigenetic organization and regulation of satellite DNA could influence chromosome stability and lead to aneuploidy. In this review, we argue that the complete annotation of satellite DNA on sex chromosomes in human, and especially in centromeric regions, will aid in explaining the prevalence and the consequences of sex chromosome aneuploidies.
- MeSH
- aneuploidie MeSH
- centromera genetika MeSH
- heterochromatin * genetika MeSH
- lidé MeSH
- lidské chromozomy MeSH
- pohlavní chromozomy genetika MeSH
- satelitní DNA * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The essential role of mammary gland stroma in the regulation of mammary epithelial development, function, and cancer has long been recognized. Only recently, though, the functions of individual stromal cell populations have begun to become more clarified. Mammary fibroblasts have emerged as master regulators and modulators of epithelial cell behavior through paracrine signaling, extracellular matrix production and remodeling, and through regulation of other stromal cell types. In this review article, we summarize the crucial studies that helped to untangle the roles of fibroblasts in mammary gland development. Furthermore, we discuss the origin, heterogeneity, and plasticity of mammary fibroblasts during mammary development and cancer progression.
- MeSH
- fibroblasty metabolismus MeSH
- lidé MeSH
- mléčné žlázy lidské růst a vývoj MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cullin-RING ubiquitin ligases (CRLs) represent the largest family of E3 ubiquitin ligases that control most if not all cellular processes. In CUL3-based CRLs, the substrate specificity is conferred by the interaction with one of around 183 existing BTB proteins, implying a broad spectrum of possible ubiquitylation signals and possible direct ubiquitylation substrates. Indeed, CUL3-based E3-ligases can catalyze various proteolytic and non-proteolytic ubiquitin signals regulating many physiological and pathophysiological states. Here, we discuss the recent studies focusing on the non-proteolytic CUL3-based signaling in mammalian cells, which emerge as important pathways during cell division, embryonic development as well as other biological processes. Mechanistically, non-proteolytic ubiquitin signals generated by CUL3 E3-ligases often regulate substrates' interactions with other downstream factors or their subcellular localization. Existing data also demonstrate an interplay with the proteolytic ubiquitylation catalyzed on the same substrates by different E3-ligases or by the same CUL3-BTB CRL3s on different substrates. In future, a deeper understanding of the upstream spatiotemporal regulatory mechanisms will help to dissect this fascinating CUL3 ubiquitin code.
- MeSH
- kulinové proteiny metabolismus MeSH
- lidé MeSH
- proteolýza MeSH
- ubikvitin metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
The gut is the biggest immune organ in the body that encloses commensal microbiota which aids in food digestion. Paneth cells, positioned at the frontline of host-microbiota interphase, can modulate the composition of microbiota. Paneth cells achieve this via the delivery of microbicidal substances, among which enteric α-defensins play the primary role. If microbiota is dysregulated, it can impact the function of the local mucosal immune system. Importantly, this system is also exposed to an enormous number of antigens which are derived from the gut-resident microbiota and processed food, and may potentially trigger undesirable local inflammatory responses. To understand the intricate regulations and liaisons between Paneth cells, microbiota and the immune system in this intestinal-specific setting, one must consider their mode of interaction in a wider context of regulatory processes which impose immune tolerance not only to self, but also to microbiota and food-derived antigens. These include, but are not limited to, tolerogenic mechanisms of central tolerance in the thymus and peripheral tolerance in the secondary lymphoid organs, and the intestine itself. Defects in these processes can compromise homeostasis in the intestinal mucosal immunity. In this review, which is focused on tolerance to intestinal antigens and its relevance for the pathogenesis of gut immune diseases, we provide an outline of such multilayered immune control mechanisms and highlight functional links that underpin their cooperative nature.
- MeSH
- alfa-defensiny biosyntéza imunologie farmakologie MeSH
- centrální tolerance MeSH
- dysbióza imunologie mikrobiologie prevence a kontrola MeSH
- exprese genu imunologie MeSH
- gastrointestinální trakt účinky léků imunologie mikrobiologie MeSH
- homeostáza imunologie MeSH
- lidé MeSH
- Panethovy buňky účinky léků imunologie mikrobiologie MeSH
- periferní tolerance * MeSH
- regulační T-lymfocyty imunologie mikrobiologie MeSH
- slizniční imunita účinky léků MeSH
- střevní mikroflóra imunologie MeSH
- symbióza imunologie MeSH
- zánět MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Highly Ca2+ selective channels trigger a large variety of cellular signaling processes in both excitable and non-excitable cells. Among these channels, the Orai channel is unique in its activation mechanism and its structure. It mediates Ca2+ influx into the cytosol with an extremely small unitary conductance over longer time-scales, ranging from minutes up to several hours. Its activation is regulated by the Ca2+ content of the endoplasmic reticulum (ER). Depletion of luminal [Ca2+]ER is sensed by the STIM1 single transmembrane protein that directly binds and gates the Orai1 channel. Orai mediated Ca2+ influx increases cytosolic Ca2+ from 100 nM up to low micromolar range close to the pore and thereby forms Ca2+ microdomains. Hence, these features of the Orai channel can trigger long-term signaling processes without affecting the overall Ca2+ content of a single living cell. Here we focus on the architecture and dynamic conformational changes within the Orai channel. This review summarizes current achievements of molecular dynamics simulations in combination with live cell recordings to address gating and permeation of the Orai channel with molecular precision.
Zygotic genome activation (ZGA) denotes the initiation of gene expression after fertilization. It is part of the complex oocyte-to-embryo transition (OET) in which a highly specialized cell - the oocyte - is fertilized and transformed into a zygote that gives rise to an embryo that will develop into a newborn. From the perspective of gene expression, the OET reflects reprogramming of germ cell gene expression into the new developmental program of the zygote. This reprogramming occurs at transcriptional and post-transcriptional levels. This review will discuss selected aspects of mammalian ZGA, highlighting shared features and evolved differences observed in commonly investigated mammals and non-mammalian model animals.
Split gene architecture of most human genes requires removal of intervening sequences by mRNA splicing that occurs on large multiprotein complexes called spliceosomes. Mutations compromising several spliceosomal components have been recorded in degenerative syndromes and haematological neoplasia, thereby highlighting the importance of accurate splicing execution in homeostasis of assorted adult tissues. Moreover, insufficient splicing underlies defective development of craniofacial skeleton and upper extremities. This review summarizes recent advances in the understanding of splicing factor function deduced from cryo-EM structures. We combine these data with the characterization of splicing factors implicated in hereditary or somatic disorders, with a focus on potential functional consequences the mutations may elicit in spliceosome assembly and/or performance. Given aberrant splicing or perturbations in splicing efficiency substantially underpin disease pathogenesis, profound understanding of the mis-splicing principles may open new therapeutic vistas. In three major sections dedicated to retinal dystrophies, hereditary acrofacial syndromes, and haematological malignancies, we delineate the noticeable variety of conditions associated with dysfunctional splicing and accentuate recurrent patterns in splicing defects.
- MeSH
- elektronová kryomikroskopie MeSH
- konformace proteinů MeSH
- lidé MeSH
- mutace MeSH
- nemoc genetika MeSH
- prekurzory RNA genetika MeSH
- ribonukleoproteiny malé jaderné chemie genetika ultrastruktura MeSH
- sestřih RNA * MeSH
- spliceozomy genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
From an evolutionary perspective, ageing is a decrease in fitness with chronological age - expressed by an increase in mortality risk and/or decline in reproductive success and mediated by deterioration of functional performance. While this makes ageing intuitively paradoxical - detrimental to individual fitness - evolutionary theory offers answers as to why ageing has evolved. In this review, I first briefly examine the classic evolutionary theories of ageing and their empirical tests, and highlight recent findings that have advanced our understanding of the evolution of ageing (condition-dependent survival, positive pleiotropy). I then provide an overview of recent theoretical extensions and modifications that accommodate those new discoveries. I discuss the role of indeterminate (asymptotic) growth for lifetime increases in fecundity and ageing trajectories. I outline alternative views that challenge a universal existence of senescence - namely the lack of a germ-soma distinction and the ability of tissue replacement and retrogression to younger developmental stages in modular organisms. I argue that rejuvenation at the organismal level is plausible, but includes a return to a simple developmental stage. This may exempt a particular genotype from somatic defects but, correspondingly, removes any information acquired during development. A resolution of the question of whether a rejuvenated individual is the same entity is central to the recognition of whether current evolutionary theories of ageing, with their extensions and modifications, can explain the patterns of ageing across the Tree of Life.
- MeSH
- biologická adaptace genetika MeSH
- biologická evoluce * MeSH
- fertilita genetika MeSH
- genetická pleiotropie MeSH
- lidé MeSH
- mutace * MeSH
- omlazení fyziologie MeSH
- rozmnožování genetika MeSH
- stárnutí genetika MeSH
- zárodečné buňky růst a vývoj metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Rhomboid-family intramembrane serine proteases are evolutionarily widespread. Their functions in different organisms are gradually being uncovered and already suggest medical relevance for infectious diseases and cancer. In contrast to these advances, selective inhibitors that could serve as efficient tools for investigation of physiological functions of rhomboids, validation of their disease relevance or as templates for drug development are lacking. In this review I extract what is known about rhomboid protease mechanism and specificity, examine the currently used inhibitors, their mechanism of action and limitations, and conclude by proposing routes for future development of rhomboid protease inhibitors.
- MeSH
- cílená molekulární terapie * MeSH
- enzymatické testy MeSH
- inhibitory proteas chemie terapeutické užití MeSH
- lidé MeSH
- membránové proteiny antagonisté a inhibitory metabolismus MeSH
- substrátová specifita MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
