Showing papers in "Development in 2014"
TL;DR: An overview of regulatory mechanisms and important developmental processes controlled by TAZ and YAP is provided and it is outlined that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors.
Abstract: Studies over the past 20 years have defined the Hippo signaling pathway as a major regulator of tissue growth and organ size. Diverse roles for the Hippo pathway have emerged, the majority of which in vertebrates are determined by the transcriptional regulators TAZ and YAP (TAZ/YAP). Key processes regulated by TAZ/YAP include the control of cell proliferation, apoptosis, movement and fate. Accurate control of the levels and localization of these factors is thus essential for early developmental events, as well as for tissue homeostasis, repair and regeneration. Recent studies have revealed that TAZ/YAP activity is regulated by mechanical and cytoskeletal cues as well as by various extracellular factors. Here, I provide an overview of these and other regulatory mechanisms and outline important developmental processes controlled by TAZ and YAP.
539 citations
TL;DR: The diversity of neocortical neural progenitors, their interspecies variations and their roles in determining the evolutionary increase in neuron numbers and neocortex size are reviewed.
Abstract: The neocortex is the seat of higher cognitive functions and, in evolutionary terms, is the youngest part of the mammalian brain. Since its origin, the neocortex has expanded in several mammalian lineages, and this is particularly notable in humans. This expansion reflects an increase in the number of neocortical neurons, which is determined during development and primarily reflects the number of neurogenic divisions of distinct classes of neural progenitor cells. Consequently, the evolutionary expansion of the neocortex and the concomitant increase in the numbers of neurons produced during development entail interspecies differences in neural progenitor biology. Here, we review the diversity of neocortical neural progenitors, their interspecies variations and their roles in determining the evolutionary increase in neuron numbers and neocortex size.
512 citations
TL;DR: It is concluded that ROS signaling is an emerging key regulator of multiple stem cell populations and the implications for reprogramming and stem cell ageing are discussed.
Abstract: An appropriate balance between self-renewal and differentiation is crucial for stem cell function during both early development and tissue homeostasis throughout life. Recent evidence from both pluripotent embryonic and adult stem cell studies suggests that this balance is partly regulated by reactive oxygen species (ROS), which, in synchrony with metabolism, mediate the cellular redox state. In this Primer, we summarize what ROS are and how they are generated in the cell, as well as their downstream molecular targets. We then review recent findings that provide molecular insights into how ROS signaling can influence stem cell homeostasis and lineage commitment, and discuss the implications of this for reprogramming and stem cell ageing. We conclude that ROS signaling is an emerging key regulator of multiple stem cell populations.
468 citations
TL;DR: This Review highlights recent advances in the understanding of lung development and regeneration, which will hopefully lead to better insights into both congenital and acquired lung diseases.
Abstract: The respiratory system, which consists of the lungs, trachea and associated vasculature, is essential for terrestrial life. In recent years, extensive progress has been made in defining the temporal progression of lung development, and this has led to exciting discoveries, including the derivation of lung epithelium from pluripotent stem cells and the discovery of developmental pathways that are targets for new therapeutics. These discoveries have also provided new insights into the regenerative capacity of the respiratory system. This Review highlights recent advances in our understanding of lung development and regeneration, which will hopefully lead to better insights into both congenital and acquired lung diseases.
446 citations
TL;DR: Understanding both the common themes and the variations in apical constriction mechanisms promises to provide insight into the mechanics that underlie tissue morphogenesis.
Abstract: Apical constriction is a cell shape change that promotes tissue remodeling in a variety of homeostatic and developmental contexts, including gastrulation in many organisms and neural tube formation in vertebrates In recent years, progress has been made towards understanding how the distinct cell biological processes that together drive apical constriction are coordinated These processes include the contraction of actin-myosin networks, which generates force, and the attachment of actin networks to cell-cell junctions, which allows forces to be transmitted between cells Different cell types regulate contractility and adhesion in unique ways, resulting in apical constriction with varying dynamics and subcellular organizations, as well as a variety of resulting tissue shape changes Understanding both the common themes and the variations in apical constriction mechanisms promises to provide insight into the mechanics that underlie tissue morphogenesis
408 citations
TL;DR: This Review highlights recent advances made in understanding piRNA function, highlighting the divergent nature of piRNA biogenesis in different organisms, and discussing the mechanisms of piRNAs action during transcriptional regulation and in transgenerational epigenetic inheritance.
Abstract: Distinguishing self from non-self plays a crucial role in safeguarding the germlines of metazoa from mobile DNA elements. Since their discovery less than a decade ago, Piwi-interacting RNAs (piRNAs) have been shown to repress transposable elements in the germline and, hence, have been at the forefront of research aimed at understanding the mechanisms that maintain germline integrity. More recently, roles for piRNAs in gene regulation have emerged. In this Review, we highlight recent advances made in understanding piRNA function, highlighting the divergent nature of piRNA biogenesis in different organisms, and discussing the mechanisms of piRNA action during transcriptional regulation and in transgenerational epigenetic inheritance.
361 citations
TL;DR: It is reported that small aggregates of mESCs self-organise into polarised structures that exhibit collective behaviours reminiscent of those that cells exhibit in early mouse embryos, including symmetry breaking, axial organisation, germ layer specification and cell behaviour, as well as axis elongation.
Abstract: Mouse embryonic stem cells (mESCs) are clonal populations derived from preimplantation mouse embryos that can be propagated in vitro and, when placed into blastocysts, contribute to all tissues of the embryo and integrate into the normal morphogenetic processes, i.e. they are pluripotent. However, although they can be steered to differentiate in vitro into all cell types of the organism, they cannot organise themselves into structures that resemble embryos. When aggregated into embryoid bodies they develop disorganised masses of different cell types with little spatial coherence. An exception to this rule is the emergence of retinas and anterior cortex-like structures under minimal culture conditions. These structures emerge from the cultures without any axial organisation. Here, we report that small aggregates of mESCs, of about 300 cells, self-organise into polarised structures that exhibit collective behaviours reminiscent of those that cells exhibit in early mouse embryos, including symmetry breaking, axial organisation, germ layer specification and cell behaviour, as well as axis elongation. The responses are signal specific and uncouple processes that in the embryo are tightly associated, such as specification of the anteroposterior axis and anterior neural development, or endoderm specification and axial elongation. We discuss the meaning and implications of these observations and the potential uses of these structures which, because of their behaviour, we suggest to call ‘gastruloids’.
335 citations
TL;DR: It is concluded that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.
Abstract: The hedgehog (HH) pathway is well known for its mitogenic and morphogenic functions during development, and HH signaling continues in discrete populations of cells within many adult mammalian tissues. Growing evidence indicates that HH regulates diverse quiescent stem cell populations, but the exact roles that HH signaling plays in adult organ homeostasis and regeneration remain poorly understood. Here, we review recently identified functions of HH in modulating the behavior of tissue-specific adult stem and progenitor cells during homeostasis, regeneration and disease. We conclude that HH signaling is a key factor in the regulation of adult tissue homeostasis and repair, acting via multiple different routes to regulate distinct cellular outcomes, including maintenance of plasticity, in a context-dependent manner.
333 citations
TL;DR: It is concluded that epithelial Wnts are dispensable and that stromal production of WNTs can fully support normal murine intestinal homeostasis.
Abstract: Wnt/β-catenin signaling supports intestinal homeostasis by regulating proliferation in the crypt. Multiple Wnts are expressed in Paneth cells as well as other intestinal epithelial and stromal cells. Ex vivo, Wnts secreted by Paneth cells can support intestinal stem cells when Wnt signaling is enhanced with supplemental R-Spondin 1 (RSPO1). However, in vivo, the source of Wnts in the stem cell niche is less clear. Genetic ablation of Porcn, an endoplasmic reticulum resident O-acyltransferase that is essential for the secretion and activity of all vertebrate Wnts, confirmed the role of intestinal epithelial Wnts in ex vivo culture. Unexpectedly, mice lacking epithelial Wnt activity (Porcn(Del)/Villin-Cre mice) had normal intestinal proliferation and differentiation, as well as successful regeneration after radiation injury, indicating that epithelial Wnts are dispensable for these processes. Consistent with a key role for stroma in the crypt niche, intestinal stromal cells endogenously expressing Wnts and Rspo3 support the growth of Porcn(Del) organoids ex vivo without RSPO1 supplementation. Conversely, increasing pharmacologic PORCN inhibition, affecting both stroma and epithelium, reduced Lgr5 intestinal stem cells, inhibited recovery from radiation injury, and at the highest dose fully blocked intestinal proliferation. We conclude that epithelial Wnts are dispensable and that stromal production of Wnts can fully support normal murine intestinal homeostasis.
292 citations
TL;DR: A cellular and molecular link between components of the inflammation response and regeneration in adult zebrafish is provided and Wnt/β-catenin is identified as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype.
Abstract: Neutrophils and macrophages, as key mediators of inflammation, have defined functionally important roles in mammalian tissue repair. Although recent evidence suggests that similar cells exist in zebrafish and also migrate to sites of injury in larvae, whether these cells are functionally important for wound healing or regeneration in adult zebrafish is unknown. To begin to address these questions, we first tracked neutrophils (lyzC+, mpo+) and macrophages (mpeg1+) in adult zebrafish following amputation of the tail fin, and detailed a migratory timecourse that revealed conserved elements of the inflammatory cell response with mammals. Next, we used transgenic zebrafish in which we could selectively ablate macrophages, which allowed us to investigate whether macrophages were required for tail fin regeneration. We identified stage-dependent functional roles of macrophages in mediating fin tissue outgrowth and bony ray patterning, in part through modulating levels of blastema proliferation. Moreover, we also sought to detail molecular regulators of inflammation in adult zebrafish and identified Wnt/β-catenin as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype. These results provide a cellular and molecular link between components of the inflammation response and regeneration in adult zebrafish.
287 citations
TL;DR: In human embryonic stem cells, the dCas9 effectors can exert positive or negative regulation on the expression of developmentally relevant genes, which can influence cell differentiation status when impinging on a key node in the regulatory network that governs the cell state.
Abstract: The identification of the trans-acting factors and cis-regulatory modules that are involved in human pluripotent stem cell (hPSC) maintenance and differentiation is necessary to dissect the operating regulatory networks in these processes and thereby identify nodes where signal input will direct desired cell fate decisions in vitro or in vivo. To deconvolute these networks, we established a method to influence the differentiation state of hPSCs with a CRISPR-associated catalytically inactive dCas9 fused to an effector domain. In human embryonic stem cells, we find that the dCas9 effectors can exert positive or negative regulation on the expression of developmentally relevant genes, which can influence cell differentiation status when impinging on a key node in the regulatory network that governs the cell state. This system provides a platform for the interrogation of the underlying regulators governing specific differentiation decisions, which can then be employed to direct cellular differentiation down desired pathways.
TL;DR: The understanding of the transcriptional control of ciliary biogenesis is reviewed, highlighting the activities of FOXJ1 and the RFX family of transcriptional regulators and how a number of signaling pathways, and lineage and cell fate determinants can induce and modulate ciliogenic programs to bring about the differentiation of distinct cilia types.
Abstract: Cilia play many essential roles in fluid transport and cellular locomotion, and as sensory hubs for a variety of signal transduction pathways. Despite having a conserved basic morphology, cilia vary extensively in their shapes and sizes, ultrastructural details, numbers per cell, motility patterns and sensory capabilities. Emerging evidence indicates that this diversity, which is intimately linked to the different functions that cilia perform, is in large part programmed at the transcriptional level. Here, we review our understanding of the transcriptional control of ciliary biogenesis, highlighting the activities of FOXJ1 and the RFX family of transcriptional regulators. In addition, we examine how a number of signaling pathways, and lineage and cell fate determinants can induce and modulate ciliogenic programs to bring about the differentiation of distinct cilia types.
TL;DR: It is shown by phenotypic rescue that the CRISPR/Cas system can be used to target and repair a premature stop codon at the albino (alb) locus in zebrafish with high efficiency and precision.
Abstract: The introduction of engineered site-specific DNA endonucleases has brought precise genome editing in many model organisms and human cells into the realm of possibility. In zebrafish, loss-of-function alleles have been successfully produced; however, germ line transmission of functional targeted knock-ins of protein tags or of SNP exchanges have not been reported. Here we show by phenotypic rescue that the CRISPR/Cas system can be used to target and repair a premature stop codon at the albino (alb) locus in zebrafish with high efficiency and precision. Using circular donor DNA containing CRISPR target sites we obtain close to 50% of larvae with precise homology-directed repair of the albb4 mutation, a small fraction of which transmitted the repaired allele in the germ line to the next generation (3/28 adult fish). The in vivo demonstration of germ line transmission of a precise SNP exchange in zebrafish underscores its suitability as a model for genetic research.
TL;DR: It is demonstrated that the neonatal mouse cochlea is capable of spontaneous hair cell regeneration after damage in vivo, which might shed light on the competence of supporting cells to regenerate hair cells and on the factors that promote the survival of newly regenerated hair cells.
Abstract: Loss of cochlear hair cells in mammals is currently believed to be permanent, resulting in hearing impairment that affects more than 10% of the population. Here, we developed two genetic strategies to ablate neonatal mouse cochlear hair cells in vivo. Both Pou4f3 DTR/+ and Atoh1-CreER TM ; ROSA26 DTA/+ alleles allowed selective and inducible hair cell ablation. After hair cell loss was induced at birth, we observed spontaneous regeneration of hair cells. Fate-mapping experiments demonstrated that neighboring supporting cells acquired a hair cell fate, which increased in a basal to apical gradient, averaging over 120 regenerated hair cells per cochlea. The normally mitotically quiescent supporting cells proliferated after hair cell ablation. Concurrent fate mapping and labeling with mitotic tracers showed that regenerated hair cells were derived by both mitotic regeneration and direct transdifferentiation. Over time, regenerated hair cells followed a similar pattern of maturation to normal hair cell development, including the expression of prestin, a terminal differentiation marker of outer hair cells, although many new hair cells eventually died. Hair cell regeneration did not occur when ablation was induced at one week of age. Our findings demonstrate that the neonatal mouse cochlea is capable of spontaneous hair cell regeneration after damage in vivo. Thus, future studies on the neonatal cochlea might shed light on the competence of supporting cells to regenerate hair cells and on the factors that promote the survival of newly regenerated hair cells.
TL;DR: It is shown that Mll2, one of the six Set1/Trithorax-type H3K4 methyltransferases in mammals, is required for trimethylation of bivalent promoters in mouse embryonic stem cells and proposed that MLL2 is the pioneer trimethyltransferase for promoter definition in the naïve epigenome and that Polycomb group action on bivalent promoter blocks the premature establishment of active, Set1C-bound, promoters.
Abstract: Trimethylation of histone H3 lysine 4 (H3K4me3) at the promoters of actively transcribed genes is a universal epigenetic mark and a key product of Trithorax group action. Here, we show that Mll2, one of the six Set1/Trithorax-type H3K4 methyltransferases in mammals, is required for trimethylation of bivalent promoters in mouse embryonic stem cells. Mll2 is bound to bivalent promoters but also to most active promoters, which do not require Mll2 for H3K4me3 or mRNA expression. By contrast, the Set1 complex (Set1C) subunit Cxxc1 is primarily bound to active but not bivalent promoters. This indicates that bivalent promoters rely on Mll2 for H3K4me3 whereas active promoters have more than one bound H3K4 methyltransferase, including Set1C. Removal of Mll1, sister to Mll2, had almost no effect on any promoter unless Mll2 was also removed, indicating functional backup between these enzymes. Except for a subset, loss of H3K4me3 on bivalent promoters did not prevent responsiveness to retinoic acid, thereby arguing against a priming model for bivalency. In contrast, we propose that Mll2 is the pioneer trimethyltransferase for promoter definition in the naive epigenome and that Polycomb group action on bivalent promoters blocks the premature establishment of active, Set1C-bound, promoters.
TL;DR: An overview of the key features of T-box transcription factors is provided and their roles and mechanisms of action during various stages of development and in stem/progenitor cell populations are highlighted.
Abstract: The T-box family of transcription factors exhibits widespread involvement throughout development in all metazoans. T-box proteins are characterized by a DNA-binding motif known as the T-domain that binds DNA in a sequence-specific manner. In humans, mutations in many of the genes within the T-box family result in developmental syndromes, and there is increasing evidence to support a role for these factors in certain cancers. In addition, although early studies focused on the role of T-box factors in early embryogenesis, recent studies in mice have uncovered additional roles in unsuspected places, for example in adult stem cell populations. Here, I provide an overview of the key features of T-box transcription factors and highlight their roles and mechanisms of action during various stages of development and in stem/progenitor cell populations.
TL;DR: A nodule fate map was produced that showed, among other things, that intracellular release of rhizobia in primordium cells and meristem daughter cells are regulated in a different manner.
Abstract: Legume root nodules are induced by N-fixing rhizobium bacteria that are hosted in an intracellular manner. These nodules are formed by reprogramming differentiated root cells. The model legume Medicago truncatula forms indeterminate nodules with a meristem at their apex. This organ grows by the activity of the meristem that adds cells to the different nodule tissues. In Medicago sativa it has been shown that the nodule meristem is derived from the root middle cortex. During nodule initiation, inner cortical cells and pericycle cells are also mitotically activated. However, whether and how these cells contribute to the mature nodule has not been studied. Here, we produce a nodule fate map that precisely describes the origin of the different nodule tissues based on sequential longitudinal sections and on the use of marker genes that allow the distinction of cells originating from different root tissues. We show that nodule meristem originates from the third cortical layer, while several cell layers of the base of the nodule are directly formed from cells of the inner cortical layers, root endodermis and pericycle. The latter two differentiate into the uninfected tissues that are located at the base of the mature nodule, whereas the cells derived from the inner cortical cell layers form about eight cell layers of infected cells. This nodule fate map has then been used to re-analyse several mutant nodule phenotypes. This showed, among other things, that intracellular release of rhizobia in primordium cells and meristem daughter cells are regulated in a different manner.
TL;DR: The intention is to outline that there is politics beyond a unilinear future, unsustainable and unjust, consisting primarily of economic growth, and argues in favour of the ‘2015 post-development agenda’.
Abstract: This article proposes that the ‘Green Economy’ is not an adequate response to the unsustainability and inequity created by ‘development’ (a western cultural construct), and puts forward alternative socio-environmental futures to (and not of) development. ‘Sustainable development’ is an oxymoron. Therefore, instead of the ‘post-2015 development agenda’, we argue in favour of the ‘2015 post-development agenda’. We discuss Buen Vivir from Latin America, Degrowth from Europe and Ecological Swaraj (or Radical Ecological Democracy) from India. The intention is to outline that there is politics beyond a unilinear future, unsustainable and unjust, consisting primarily of economic growth.
TL;DR: The expression and localization of S1P receptors is dynamically regulated and controls vascular development, vessel stability and immune cell trafficking, and crucial events during embryogenesis, such as angiogenesis, cardiogenic, limb development and neurogenesis, are regulated by S 1P signalling.
Abstract: Sphingosine 1-phosphate (S1P) is a lipid mediator formed by the metabolism of sphingomyelin. In vertebrates, S1P is secreted into the extracellular environment and signals via G protein-coupled S1P receptors to regulate cell-cell and cell-matrix adhesion, and thereby influence cell migration, differentiation and survival. The expression and localization of S1P receptors is dynamically regulated and controls vascular development, vessel stability and immune cell trafficking. In addition, crucial events during embryogenesis, such as angiogenesis, cardiogenesis, limb development and neurogenesis, are regulated by S1P signalling. Here, and in the accompanying poster, we provide an overview of S1P signalling in development and in disease.
TL;DR: The data suggest that EpiSC pluripotency encompasses a range of reversible lineage-biased states reflecting the birth of pioneer lineage precursors from a pool of uncommitted Epi SCs similar to the earliest cell fate restriction events taking place in the gastrula stage epiblast.
Abstract: During gastrulation, epiblast cells are pluripotent and their fate is thought to be constrained principally by their position. Cell fate is progressively restricted by localised signalling cues from areas including the primitive streak. However, it is unknown whether this restriction accompanies, at the individual cell level, a reduction in potency. Investigation of these early transition events in vitro is possible via the use of epiblast stem cells (EpiSCs), self-renewing pluripotent cell lines equivalent to the postimplantation epiblast. Strikingly, mouse EpiSCs express gastrulation stage regional markers in self-renewing conditions. Here, we examined the differentiation potential of cells expressing such lineage markers. We show that undifferentiated EpiSC cultures contain a major subfraction of cells with reversible early primitive streak characteristics, which is mutually exclusive to a neural-like fraction. Using in vitro differentiation assays and embryo grafting we demonstrate that primitive streak-like EpiSCs are biased towards mesoderm and endoderm fates while retaining pluripotency. The acquisition of primitive streak characteristics by self-renewing EpiSCs is mediated by endogenous Wnt signalling. Elevation of Wnt activity promotes restriction towards primitive streak-associated lineages with mesendodermal and neuromesodermal characteristics. Collectively, our data suggest that EpiSC pluripotency encompasses a range of reversible lineage-biased states reflecting the birth of pioneer lineage precursors from a pool of uncommitted EpiSCs similar to the earliest cell fate restriction events taking place in the gastrula stage epiblast.
TL;DR: It is found that Neat1 knockout mice stochastically fail to become pregnant despite normal ovulation, suggesting that corpus luteum dysfunction and concomitant low progesterone were the primary causes of the decreased fertility.
Abstract: Neat1 is a non-protein-coding RNA that serves as an architectural component of the nuclear bodies known as paraspeckles. Although cell-based studies indicate that Neat1 is a crucial regulator of gene expression, its physiological relevance remains unclear. Here, we find that Neat1 knockout (KO) mice stochastically fail to become pregnant despite normal ovulation. Unilateral transplantation of wild-type ovaries or the administration of progesterone partially rescued the phenotype, suggesting that corpus luteum dysfunction and concomitant low progesterone were the primary causes of the decreased fertility. In contrast to the faint expression observed in most of the adult tissues, Neat1 was highly expressed in the corpus luteum, and the formation of luteal tissue was severely impaired in nearly half of the Neat1 KO mice. These observations suggest that Neat1 is essential for the formation of the corpus luteum and for the subsequent establishment of pregnancy under a suboptimal condition that has not yet been identified.
TL;DR: New studies have revealed the importance of proper expression of specific imprinted genes in induced pluripotent stem cells and in adult stem cells, highlighting the complex nature and developmental importance of imprinting genes.
Abstract: Genes that are subject to genomic imprinting in mammals are preferentially expressed from a single parental allele. This imprinted expression of a small number of genes is crucial for normal development, as these genes often directly regulate fetal growth. Recent work has also demonstrated intricate roles for imprinted genes in the brain, with important consequences on behavior and neuronal function. Finally, new studies have revealed the importance of proper expression of specific imprinted genes in induced pluripotent stem cells and in adult stem cells. As we review here, these findings highlight the complex nature and developmental importance of imprinted genes.
TL;DR: The conceptual background and evidence suggest that cytoneme-mediated signaling is a dispersal mechanism that delivers signaling proteins directly at sites of cell-cell contact.
Abstract: Development creates a vast array of forms and patterns with elegant economy, using a small vocabulary of pattern-generating proteins such as BMPs, FGFs and Hh in similar ways in many different contexts. Despite much theoretical and experimental work, the signaling mechanisms that disperse these morphogen signaling proteins remain controversial. Here, we review the conceptual background and evidence that establishes a fundamental and essential role for cytonemes as specialized filopodia that transport signaling proteins between signaling cells. This evidence suggests that cytoneme-mediated signaling is a dispersal mechanism that delivers signaling proteins directly at sites of cell-cell contact.
TL;DR: The most recent advances in understanding the mechanisms of Mediator function are described, with an emphasis on its role during development and disease.
Abstract: Mediator is a multiprotein complex that is required for gene transcription by RNA polymerase II. Multiple subunits of the complex show specificity in relaying information from signals and transcription factors to the RNA polymerase II machinery, thus enabling control of the expression of specific genes. Recent studies have also provided novel mechanistic insights into the roles of Mediator in epigenetic regulation, transcriptional elongation, termination, mRNA processing, noncoding RNA activation and super enhancer formation. Based on these specific roles in gene regulation, Mediator has emerged as a master coordinator of development and cell lineage determination. Here, we describe the most recent advances in understanding the mechanisms of Mediator function, with an emphasis on its role during development and disease.
TL;DR: The role of transcription factor heterogeneity in facilitating the intrinsically dynamic and stochastic nature of the pluripotency network, which in turn provides a potential benefit to a population of cells that needs to balance cell fate decisions is discussed.
Abstract: When pluripotent cells are exposed to a uniform culture environment they routinely display heterogeneous gene expression. Aspects of this heterogeneity, such as Nanog expression, are linked to differences in the propensity of individual cells to either self-renew or commit towards differentiation. Recent findings have provided new insight into the underlying causes of this heterogeneity, which we summarise here using Nanog, a key regulator of pluripotency, as a model gene. We discuss the role of transcription factor heterogeneity in facilitating the intrinsically dynamic and stochastic nature of the pluripotency network, which in turn provides a potential benefit to a population of cells that needs to balance cell fate decisions.
TL;DR: An overview of the mechanics, principles and regulation of actomyosin-driven cellular tension driving tissue morphogenesis is provided.
Abstract: Tissue morphogenesis is driven by coordinated cellular deformations. Recent studies have shown that these changes in cell shape are powered by intracellular contractile networks comprising actin filaments, actin cross-linkers and myosin motors. The subcellular forces generated by such actomyosin networks are precisely regulated and are transmitted to the cell cortex of adjacent cells and to the extracellular environment by adhesive clusters comprising cadherins or integrins. Here, and in the accompanying poster, we provide an overview of the mechanics, principles and regulation of actomyosin-driven cellular tension driving tissue morphogenesis.
TL;DR: Three distinct aspects of cerebellar development are explored – allocation of the Cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity – each defined by distinct regulatory mechanisms and each with special significance for health and disease.
Abstract: The cerebellum is a pre-eminent model for the study of neurogenesis and circuit assembly. Increasing interest in the cerebellum as a participant in higher cognitive processes and as a locus for a range of disorders and diseases make this simple yet elusive structure an important model in a number of fields. In recent years, our understanding of some of the more familiar aspects of cerebellar growth, such as its territorial allocation and the origin of its various cell types, has undergone major recalibration. Furthermore, owing to its stereotyped circuitry across a range of species, insights from a variety of species have contributed to an increasingly rich picture of how this system develops. Here, we review these recent advances and explore three distinct aspects of cerebellar development - allocation of the cerebellar anlage, the significance of transit amplification and the generation of neuronal diversity - each defined by distinct regulatory mechanisms and each with special significance for health and disease.
TL;DR: Recent advances in the field as well as the mechanistic steps involved in this phenomenon have shed light on how and why cell competition exists in developing and adult organisms.
Abstract: A conventional view of development is that cells cooperate to build an organism. However, based on studies of Drosophila, it has been known for years that viable cells can be eliminated by their neighbours through a process termed cell competition. New studies in mammals have revealed that this process is universal and that many factors and mechanisms are conserved. During cell competition, cells with lower translation rates or those with lower levels of proteins involved in signal transduction, polarity and cellular growth can survive in a homogenous environment but are killed when surrounded by cells of higher fitness. Here, we discuss recent advances in the field as well as the mechanistic steps involved in this phenomenon, which have shed light on how and why cell competition exists in developing and adult organisms.
TL;DR: Recent advances in the understanding of how plant hormones, transcriptional regulators and mechanical properties of the tissue modulate leaf development are reviewed to yield a substantial diversity of leaf forms.
Abstract: The development of plant leaves follows a common basic program that is flexible and is adjusted according to species, developmental stage and environmental circumstances. Leaves initiate from the flanks of the shoot apical meristem and develop into flat structures of variable sizes and forms. This process is regulated by plant hormones, transcriptional regulators and mechanical properties of the tissue. Here, we review recent advances in the understanding of how these factors modulate leaf development to yield a substantial diversity of leaf forms. We discuss these issues in the context of leaf initiation, the balance between morphogenesis and differentiation, and patterning of the leaf margin.
TL;DR: The molecular functions of Pax genes during development are reviewed and the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages are detailed.
Abstract: Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer.