The stunning possibility of “reprogramming” differentiated somatic cells to express a pluripotent stem cell phenotype (iPS, induced pluripotent stem cell) and the “ground state” character of pluripotency reveal fundamental features of cell fate regulation that lie beyond existing paradigms. The rarity of reprogramming events appears to contradict the robustness with which the unfathomably complex phenotype of stem cells can reliably be generated. This apparent paradox, however, is naturally explained by the rugged “epigenetic landscape” with valleys representing (...) “preprogrammed” attractor states that emerge from the dynamical constraints of the gene regulatory network. This article provides a pedagogical primer to the fundamental principles of gene regulatory networks as integrated dynamic systems and reviews recent insights in gene expression noise and fate determination, thereby offering a formal framework that may help us to understand why cell fate reprogramming events are inherently rare and yet so robust. (shrink)

The Drosophila tracheal system is a branched tubular structure that supplies air to target tissues. The elaborate tracheal morphology is shaped by two linked inductive processes, one involving the choice of cell fates, and the other a guided cell migration. We will describe the molecular basis for these processes, and the allocation of cell fate decisions to four temporal hierarchies. First, tracheal placodes are specified within the embryonic ectoderm. Subsequently, branch fates are allocated within the tracheal (...) placodes, prior to migration. Localized presentation of the FGF ligand, Branchless, to tracheal cells that express the FGF receptor, Breathless, guides migration. Once cell migration is initiated, distinct cell fates are determined within each migrating branch. Finally, inhibitory feedback mechanisms ensure the correct assignment of these fates. Tracheal cell fate choices are determined by signaling cascades triggered by signals emanating from the tracheal cells, as well as by ligands produced by adjacent tissues. BioEssays 22:219–226, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Mild and massive DNA damage are differentially integrated into the cellular signaling networks and, in consequence, provoke different cell fate decisions. After mild damage, the tumor suppressor p53 directs the cellular response to cell cycle arrest, DNA repair, and cell survival, whereas upon severe damage, p53 drives the cell death response. One posttranslational modification of p53, phosphorylation at Serine 46, selectively occurs after severe DNA damage and is envisioned as a marker of the cell (...) death response. However, the molecular mechanism of action of the p53 Ser46 phospho‐isomer, the molecular timing of this phosphorylation event, and its activating effects on apoptosis and ferroptosis still await exploration. In this essay, the current body of evidence on the molecular function of this deadly p53 mark, its evolutionary conservation, and the regulation of the key players of this response, the p53 Serine 46 kinases, are reviewed and dissected. (shrink)

Targeted transitions in chromatin states at thousands of genes are essential drivers of eukaryotic development. Therefore, understanding the in vivo dynamics of epigenetic regulators is crucial for deciphering the mechanisms underpinning cell fate decisions. This review illustrates how, in addition to its cell memory function, the Polycomb group of transcriptional regulators orchestrates temporal, cell and tissue‐specific expression of master genes during development. These highly sophisticated developmental transitions are dependent on the context‐ and tissue‐specific assembly of the (...) different types of Polycomb Group (PcG) complexes, which regulates their targeting and/or activities on chromatin. Here, an overview is provided of how PcG complexes function at multiple scales to regulate transcription, local chromatin environment, and higher order structures that support normal differentiation and are perturbed in tumorigenesis. (shrink)

Stomata, the most influential components in gas exchange with the atmosphere, represent a revealing system for studying cell fate determination. Studies in Arabidopsis thaliana have demonstrated that many of the components, functioning in a signaling cascade, guide numerous cell fate transitions that occur during stomatal development. The signaling cascade is initiated at the cell surface through the activation of the membrane receptors TOO MANY MOUTHS (TMM) and/or ERECTA (ER) family members by the secretory peptide EPIDERMAL (...) PATTERNING FACTOR1 (EPF1) and/or a substrate processed proteolytically by the subtilase STOMATAL DENSITY AND DISTRIBUTION1 (SDD1) and transduced through cytoplasmic MAP kinases (YODA (YDA), MKK4/MKK5, and MPK3/MPK6) towards the nucleus. In the nucleus, these MAP kinases regulate the activity of the basic helix‐loop‐helix (bHLH) proteins SPEECHLESS (SPCH), MUTE, and FAMA, which act in concert with the bHLH‐Leu zipper protein SCREAM (SCRM) (and/or its closely related paralog, SCREAM2). This article reviews current insights into the role of this signaling cascade during stomatal development. (shrink)

The C. elegans male tail is being studied as a model to understand how genes specify the form of multicellular animals. Morphogenesis of the specialized male copulatory organ takes place in the last larval stages during male development. Genetic analysis is facilitated because the structure is not necessary for male viability or for strain propagation. Analysis of developmental mutants, isolated in several functional and morphological screens, has begun to reveal how fates of cells are determined in the cell lineages, (...) and how the specification of cell fates affects the morphology of the structure. Cytological studies in wild type and in mutants have been used to study the mechanism of pattern formation in the tail peripheral nervous system. The ultimate goal is to define the entire pathway leading to the male copulatory organ. (shrink)

Transcriptional networks regulate cell fate decisions, which occur at the level of individual cells. However, much of what we know about their structure and function comes from studies averaging measurements over large populations of cells, many of which are functionally heterogeneous. Such studies conceal the variability between cells and so prevent us from determining the nature of heterogeneity at the molecular level. In recent years, many protocols and platforms have been developed that allow the high throughput analysis of (...) gene expression in single cells, opening the door to a new era of biology. Here, we discuss the need for single cell gene expression analysis to gain deeper insights into the transcriptional control of cell fate decisions, and consider the insights it has provided so far into transcriptional regulatory networks in development. (shrink)

The fate of cells arrested in mitosis by antimitotic compounds is complex but is influenced by competition between pathways promoting cell death and pathways promoting mitotic exit. As components of both of these pathways are regulated by Cdc20‐dependent degradation, I hypothesize that variations in Cdc20 protein levels, rather than mutations in checkpoint genes, could affect cell fate during prolonged mitotic arrest. This hypothesis is supported by experiments where manipulation of Cdc20 levels affects the response to antimitotic (...) compounds. The observed differences in Cdc20 levels between cell lines likely reflects differences in the rate of synthesis or degradation of the protein; therefore, understanding these pathways at a molecular level could pave the way for modulating the activity of Cdc20, in turn presenting novel therapeutic possibilities. (shrink)

Neural crest cells are multipotent progenitors, capable of producing diverse cell types upon differentiation. Recent studies have identified significant heterogeneity in both the fates produced and genes expressed by different premigratory crest cells. While these cells may be specified toward particular fates prior to migration, transplant studies show that some may still be capable of respecification at this time. Here we summarize evidence that extracellular signals in the local environment may act to specify premigratory crest and thus generate diversity (...) in the population. Three main classes of signals–Wnts, BMP2/BMP4 and TGFβ1,2,3–have been shown to directly influence the production of particular neural crest cell fates, and all are expressed near the premigratory crest. This system may therefore provide a good model for integration of multiple signaling pathways during embryonic cell fate specification. BioEssays 22:708–716, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Classical embryological studies have provided a great deal of information on the autonomy and stability of cell fate determination in early sea urchin embryos. However, these studies were limited by the tools available at the time, and the interpretation of the results of these experiments was limited by the lack of information available at the molecular level. Recent studies which have re‐examined classical experiments at the molecular level have provided important new insights into the mechanism of determination in (...) sea urchins, and require us to re‐evaluate some long standing theories on the process of differentiation. (shrink)

Determination of cell fate in the developing eye of Drosophila depends on a precise sequence of cellular interactions which generate the stereotypic array of ommatidia. In the eye imaginal disc, an initially unpatterned epithelial sheath of cells, the first step in this process may be the specification of R8 photoreceptor cells at regular intervals. Genes such as Notch and scabrous, known to be involved in bristle development, alos participate in this process, suggesting that the specification of ommatidial founder (...) cells and the formation of sensory organs in the adult epidermis may involve a similar mechanism, that of lateral inhibition. The subsequent steps of ommatidial assembly, following R8 assignment, involve a different mechanism: Undetermined cells read their position based on the contacts they make with neighbors that have already begun to differentiate. The development of the R7 photoreceptor cell, one of the eight photoreceptor cells in the ommatidium, is best understood. An important role seems to be played by sevenless, a receptor tyrosine kinase on the surface of the R7 precursor. It transmits the positional information– most likely encoded by the boss protein on the neighboring R8 cell membrane – into the cell via its tyrosine kinase, which activates a signal transduction cascade. Constitutive activation of the sevenless kinase by overexpression of an N‐terminally truncated form results in the diversion of other ommatidial cells into the R7 pathway suggesting that activation of the sevenless signalling pathway is sufficient to specify R7 development. Genetic dissection of this pathway should therefore identify components of a signalling cascade activated by a tyrosine kinase. (shrink)

The Drosophila Bolwig organs are small photoreceptor bundles that facilitate the phototactic behavior of the larva. Comparative literature suggests that these highly reduced visual organs share evolutionary ancestry with the adult compound eye. A recent molecular genetic study produced the first detailed account of the mechanisms controlling differential opsin expression and photoreceptor subtype determination in these enigmatic eyes of the Drosophila larva. Here, the evolutionary implications are examined, taking into account the dynamic diversification of opsin genes and the spatial regulation (...) of opsin homolog expression in other insects. It is concluded that, consistent with their common evolutionary roots, the Drosophila larval and adult eyes use the same mechanisms for the regulation of opsin expression and photoreceptor cell fate specification. Strikingly, the structurally highly derived Bolwig organs retained a more ancestral state of opsin expression and regulation. Inconspicuous in size, the Drosophila larval eyes deliver useful lessons in the reconstruction of homology between neuronal cell types with gene expression data, and on the conservative nature of gene regulatory network evolution during the emergence of novel organs from ancestral templates. BioEssays 30:980–993, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Immune cells are highly dynamic in their response to the tissue environment. Most immune cells rapidly change their metabolic profile to obtain sufficient energy to engage in defensive or homeostatic processes. Such “immunometabolism” is governed through intermediate metabolites, and has a vital role in regulating immune‐cell function. The underlying metabolic reactions are shaped by the abundance and accessibility of specific nutrients, as well as the overall metabolic status of the host. Here, we discuss how different immune‐cell types gain (...) a sufficient energy supply. We then explain how immune cells perform various functions under challenged conditions and expend energy to sustain homeostasis. Finally, we speculate on how the immune‐cell metabolic profile might be modulated in health and disease, by manipulating nutrient availability. By such intervention, the recovery of patient with dysregulated immune system responses might be sped up and the fitness of an individual efficiently restored. (shrink)

Neural crest cells are multipotent progenitors, capable of producing diverse cell types upon differentiation. Recent studies have identified significant heterogeneity in both the fates produced and genes expressed by different premigratory crest cells. While these cells may be specified toward particular fates prior to migration, transplant studies show that some may still be capable of respecification at this time. Here we summarize evidence that extracellular signals in the local environment may act to specify premigratory crest and thus generate diversity (...) in the population. Three main classes of signals–Wnts, BMP2/BMP4 and TGFβ1,2,3–have been shown to directly influence the production of particular neural crest cell fates, and all are expressed near the premigratory crest. This system may therefore provide a good model for integration of multiple signaling pathways during embryonic cell fate specification. BioEssays 22:708–716, 2000. © 2000 John Wiley & Sons, Inc. (shrink)

Development of an animal embryo involves the coordination of cell divisions, a variety of inductive interactions and extensive cellular rearrangements. One of the biggest challenges in developmental biology is to explain the relationships between these processes and the mechanisms that regulate them. Teleost embryos provide an ideal subject for the study of these issues. Their optical lucidity combined with modern techniques for the marking and observation of individual living cells allow high resolution investigations of specific morphogenetic movements and the (...) construction of detailed fate maps. In this review we describe the patterns of cell divisions, cellular movements and other morphogenetic events during zebrafish early development and discuss how these events relate to the formation of restricted lineages. (shrink)

Fezf1 and Fezf2 are highly conserved transcription factors that were first identified by their specific expression in the anterior neuroepithelium of Xenopus and zebrafish embryos. These proteins share an N‐terminal domain with homology to the canonical engrailed repressor motif and a C‐terminal DNA binding domain containing six C2H2 zinc‐finger repeats. Over a decade of study indicates that the Fez proteins play critical roles during nervous system development in species as diverse as fruit flies and mice. Herein we discuss recent progress (...) in understanding the functions of Fezf1 and Fezf2 in neurogenesis and cell fate specification during mammalian nervous system development. Going forward we believe that efforts should focus on understanding how expression of these factors is precisely regulated, and on identifying target DNA sequences and interacting partners. Such knowledge may reveal the mechanisms by which Fezf1 and Fezf2 accomplish both independent and redundant functions across diverse tissue and cell types. (shrink)

Two enzymes involved in the synthesis of pyrimidine and purine nucleotides, CTP synthase (CTPS) and IMP dehydrogenase (IMPDH), can assemble into a single or very few large filaments called rods and rings (RR) or cytoophidia. Most recently, asymmetric cytoplasmic distribution of organelles during cell division has been described as a decisive event in hematopoietic stem cell fate. We propose that cytoophidia, which could be considered as membrane‐less organelles, may also be distributed asymmetrically during mammalian cell division (...) as previously described for Schizosaccharomyces pombe. Furthermore, because each type of nucleotide intervenes in distinct processes (e.g., membrane synthesis, glycosylation, and G protein‐signaling), alterations in the rate of synthesis of specific nucleotide types could influence cell differentiation in multiple ways. Therefore, we hypothesize that whether a daughter cell inherits or not CTPS or IMPDH filaments determines its fate and that this asymmetric inheritance, together with the dynamic nature of these structures enables plasticity in a cell population. (shrink)

It is generally assumed that the developmental program of embryogenesis relies on epigenetic mechanisms. However, a mechanistic link between epigenetic marks and cell fate decisions had not been established so far. In a recent article, Torres‐Padilla and colleagues1 show that epigenetic information and, more precisely, histone arginine methylation mediated by CARM1 could contribute to cell fate decisions in the mouse 4‐cell‐stage embryo. It provides the first indications that global epigenetic information influences allocation of pluripotent cells (...) toward the first cell lineages. BioEssays 29:520–524, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

Previous work has suggested that many stem cells can be found in microanatomic niches, where adjacent somatic cells of the niche control the differentiation and proliferation states of their resident stem cells. Recently published work examining intestinal stem cells (ISCs) in the adult Drosophila midgut suggests a new paradigm where some stem cells actively control the cell fate decisions of their daughters. Here, we review recent literature(1) demonstrating that, in the absence of a detectable stem cell niche, (...) multipotent Drosophila ISCs modulate the Notch signaling pathway in their adjacent daughter cells in order to specify the differentiated lineages of their descendants. These observations made in Drosophila are challenging and advancing our understanding of stem cell biology. BioEssays 30:107–109, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Stomata are microscopic pores on the surface of land plants used for gas and water vapor exchange. A pair of highly specialized guard cells surround the pore and adjust pore size. Studies in Arabidopsis have revealed that cell–cell communication is essential to coordinate the asymmetric cell divisions required for proper stomatal patterning. Initial research in this area identified signaling molecules that negatively regulate stomatal differentiation. However, genes promoting cell‐fate transition leading to mature guard cells remained (...) elusive. Now, three closely related basic helix–loop–helix (bHLH) proteins, SPEECHLESS, MUTE and FAMA have been identified as positive regulators that direct three consecutive cell‐fate decisions during stomatal development. The identification of these genes opens a new direction to investigate the evolution of stomatal development and the conserved functions of bHLH proteins in cell type differentiation adopted by plants and animals. BioEssays 29:861–870, 2007. © 2007 Wiley Periodicals, Inc. (shrink)

In response to DNA‐damage, cells have to decide between different cell fate programmes. Activation of the tumour suppressor HIPK2 specifies the DNA damage response (DDR) and tips the cell fate balance towards an apoptotic response. HIPK2 is activated by the checkpoint kinase ATM, and triggers apoptosis through regulatory phosphorylation of a set of cellular key molecules including the tumour suppressor p53 and the anti‐apoptotic corepressor CtBP. Recent work has identified HIPK2 as a regulator of the ultimate (...) step in cytokinesis: the abscission of the mother and daughter cells. Since proper cytokinesis is essential for genome stability and maintenance of correct ploidy, this finding sheds new light on the tumour suppressor function of HIPK2. Here we highlight the molecular mechanisms coordinating HIPK2 function and discuss its emerging role as a tumour suppressor. (shrink)

A unique feature of flowering plants is their ability to produce organs continuously, for hundreds of years in some species, from actively growing tips called apical meristems. All plants possess at least one form of apical meristem, whose cells are functionally analogous to animal stem cells because they can generate specialized organs and tissues. The shoot apical meristem of angiosperm plants acts as a continuous source of pluripotent stem cells, whose descendents become incorporated into organ primordia and acquire different fates. (...) Recent studies are unveiling some of the molecular pathways that specify stem cell fate in the center of the shoot apical meristem, that confer organ founder cell fate on the periphery, and that connect meristem patterning elements with events at the cellular level. The results are providing important insights into the mechanisms through which shoot apical meristems integrate cell fate decisions with cellular proliferation and global regulation of growth and development. BioEssays 24:27–37, 2002. Published 2002 John Wiley & Sons, Inc. (shrink)

Competence is an active state that defines the way in which cells respond to an inductive signal. A challenge of developmental biology is to explain not just the nature of the signalling molecules that promote cell specification or differentiation, but also how cells acquire competence to respond to these signals and what that reflects in molecular terms. A recent paper by Carmena et al.(1) has revealed how several signalling mechanisms are used sequentially and in specific combinations to specify two (...) mesodermal lineages in Drosophila. BioEssays 21:455–458, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Stem cells did not become a proper research object until the 1960 s. Yet the term and the basic mind-set—namely the conception of single undifferentiated cells, be they embryonic or adult, as the basic units responsible for a directed process of development, differentiation and increasing specialisation—were already in place at the end of the nineteenth century and then transmitted on a non-linear path in the form of tropes and diagrams. Ernst Haeckel and August Weismann played a special role in this (...) story. The first coined the term Stammzelle (stem cell), the second was the author of the first cellular stem-tree diagram. Even today, I shall argue, the understanding of stem cells, especially the popular perception, is to a large extent a Haeckelian–Weismannian one. After having demonstrated this, by analysing the terminology, in this essay I will focus on the use of cytogenetic tree diagrams between 1892 and 1925 and on the tacit understanding of stem cells that they transmit. (shrink)

Competence is an active state that defines the way in which cells respond to an inductive signal. A challenge of developmental biology is to explain not just the nature of the signalling molecules that promote cell specification or differentiation, but also how cells acquire competence to respond to these signals and what that reflects in molecular terms. A recent paper by Carmena et al.(1) has revealed how several signalling mechanisms are used sequentially and in specific combinations to specify two (...) mesodermal lineages in Drosophila. BioEssays 21:455–458, 1999. © 1999 John Wiley & Sons, Inc. (shrink)

Alternative non‐B‐DNA conformations formed under physiological conditions by sequences called flipons include left‐handed Z‐DNA, three‐stranded triplexes, and four‐stranded i‐motifs and quadruplexes. These conformations accumulate and release energy to enable the local assembly of cellular machines in a context specific manner. In these transactions, nucleosomes store power, serving like rechargeable batteries, while flipons smooth energy flows from source to sink by acting as capacitors or resistors. Here, I review the known biological roles for flipons. I present recent and unequivocal findings showing (...) how innate immune responses are regulated by Z‐flipons that identify endogenous RNAs as self. Evidence is also presented supporting important roles for other flipon classes. In these examples, the dynamic exchange of energy between flipons and nucleosomes enables rapid switching of genetic programs without altering flipon sequence. The increased phenotypic diversity enabled by flipons drives their natural selection, with adaptations evolving faster than is possible by codon mutation alone. (shrink)

From the 1930s through the 1970s, C. H. Waddington attempted to reunite genetics, embryology, and evolution. One of the means to effect this synthesis was his model of the epigenetic landscape. This image originally recast genetic data in terms of embryological diagrams and was used to show the identity of genes and inducers and to suggest the similarities between embryological and genetic approaches to development. Later, the image became more complex and integrated gene activity and mutations. These revised epigenetic landscapes (...) presented an image of how mutations could alter developmental pathways to yield larger phenotypic changes. These diagrams became less important as the operon became used to model differential gene regulation. (shrink)

In the adult mammalian brain, neurogenesis is restricted to few regions, while gliogenesis continues in a wide‐spread manner. Here we discuss our knowledge of extrinsic and intrinsic factors regulating neuro‐ and gliogenesis in the adult brain and propose a model of fate specification identifying the states of easiest transition between glio‐ and neurogenesis, highlighting the unique mechanisms stabilising the neural stem cell state. The model also encompasses the fate alterations achieved by direct reprogramming, and hence addresses a (...) novel avenue for repair, namely eliciting neurogenesis from glial cells outside the neurogenic niches. (shrink)

Egg or sperm? The mechanism of sexual fate decision in germ cells has been a long‐standing issue in biology. A recent analysis identified foxl3 as a gene that determines the sexual fate decision of germ cells in the teleost fish, medaka. foxl3/Foxl3 acts in female germline stem cells to repress commitment into male fate (spermatogenesis), indicating that the presence of mitotic germ cells in the female is critical for continuous sexual fate decision of germ cells in (...) medaka gonads. Interestingly, foxl3 is found in most vertebrate genomes except for mammals. This provides the interesting possibility that the sexual fate of germ cells in mammals is determined in a different way compared to foxl3‐possessing vertebrates. Considering the fact that germline stem cells are the cells where foxl3 begins to express and sexual fate decision initiates and mammalian ovary does not have typical germline stem cells, the mechanism in mammals may have been co‐evolved with germline stem cell loss in mammalian ovary. (shrink)

Valuable insights into eukaryotic regulatory circuits can emerge from studying interactions of bacterial pathogens such as Helicobacter pylori with host tissues. H. pylori uses a type IV secretion system (T4SS) to deliver its CagA virulence protein to epithelial cells, where much of it becomes phosphorylated. CagA's phosphorylated and non‐phosphorylated forms each interact with host regulatory proteins to alter cell structure and cell fate. Kwok and colleagues1 showed that CagA destined for phosphorylation is delivered using host integrin as (...) receptor and H. pylori's CagL protein as an integrin‐specific adhesin, and that CagL–integrin‐binding activates the kinase cascade responsible for CagA phosphorylation. This research contributes to understanding infectious disease and the control of cell fates. BioEssays 30:515–520, 2008. © 2008 Wiley Periodicals, Inc. (shrink)

Skin pigment pattern formation is a paradigmatic example of pattern formation. In zebrafish, the adult body stripes are generated by coordinated rearrangement of three distinct pigment cell‐types, black melanocytes, shiny iridophores and yellow xanthophores. A stem cell origin of melanocytes and iridophores has been proposed although the potency of those stem cells has remained unclear. Xanthophores, however, seemed to originate predominantly from proliferation of embryonic xanthophores. Now, data from Singh et al. shows that all three cell‐types derive (...) from shared stem cells, and that these cells generate peripheral neural cell‐types too. Furthermore, clonal compositions are best explained by a progressive fate restriction model generating the individual cell‐types. The numbers of adult pigment stem cells associated with the dorsal root ganglia remain low, but progenitor numbers increase significantly during larval development up to metamorphosis, likely via production of partially restricted progenitors on the spinal nerves. (shrink)

Imagine cells that live in a high‐gradient magnetic field (HGMF). Through what mechanisms do the cells sense a non‐uniform magnetic field and how such a field changes the cell fate? We show that magnetic forces generated by HGMFs can be comparable to intracellular forces and therefore may be capable of altering the functionality of an individual cell and tissues in unprecedented ways. We identify the cellular effectors of such fields and propose novel routes in cell biology (...) predicting new biological effects such as magnetic control of cell‐to‐cell communication and vesicle transport, magnetic control of intracellular ROS levels, magnetically induced differentiation of stem cells, magnetically assisted cell division, or prevention of cells from dividing. On the basis of experimental facts and theoretical modeling we reveal timescales of cellular responses to high‐gradient magnetic fields and suggest an explicit dependence of the cell response time on the magnitude of the magnetic field gradient. (shrink)

Sex determination in mammals is mediated via the supporting cell lineage in the fetal gonad. In the very early stages of gonadal development, the fate of the supporting cell population is critically dependent on the expression of the male‐determining gene on the Y chromosome. If this gene is absent or fails to be expressed, or is expressed too late or in too small a number of supporting cells, all supporting cells (XX or XY) differentiate as pre‐follicle cells (...) and development proceeds along the female pathway. Supporting cells in which the male‐determining gene is expressed in a timely manner differentiate as pre‐Sertoli cells; given sufficient such cells, testis cords form and development proceeds in a male direction. If XX supporting cells are also present, a few may be recruited into the pre‐Sertoli population and participate in testis cord formation. The subsequent fate of pre‐follicle cells depends critically on interaction with the germ cell population in the developing gonad: absence of germ cells may lead to partial masculinization of the gonad, and/or to disappearance of the supporting cell component. (shrink)

The specification of specific and often unique fates to individual cells as a function of their position within a developing organism is a fundamental process during the development of multicellular organisms. The development of the Drosophila embryonic central nervous system serves as an excellent model system in which to clarify the developmental mechanisms that link pattern formation to cell-type specification. The Drosophila embryonic central nervous system develops from a set of neural stem cells termed neuroblasts. Neuroblasts arise from the (...) ectoderm in an invariant pattern, and each neuroblast acquires a unique fate based on its position within this pattern. Two groups of genes recently have been demonstrated to govern the individual fate specification of neuroblasts. One group, the segment polarity genes, enables neuroblasts that develop in different anteroposterior positions to acquire different fates. The second group, referred to as the columnar genes, ensures that neuroblasts that develop in different dorsoventral domains assume different fates. When integrated, the activities of the segment polarity and columnar genes create a Cartesian coordinate system that bestows unique fates to individual neuroblasts as a function of their position of formation within the ectoderm. BioEssays 1999;21:922–931. © 1999 John Wiley & Sons, Inc. (shrink)

The fate of root epidermal cells is controlled by a complex interplay of transcriptional regulators, generating a genetically determined, position‐biased arrangement of root hair cells. This pattern is altered during postembryonic development and in response to environmental signals to confer developmental plasticity that acclimates the plant to the prevailing conditions. Based on the hypothesis that events downstream of this initial mechanism can modulate the pattern installed during embryogenesis, we have developed a reaction diffusion model that reproduces the root hair (...) patterning previously observed experimentally. Under all growth conditions, an almost equal spacing between root hair forming cells was observed both in vitro and in silico, indicating that long‐range intercellular communication is crucial for the trichoblasts' decision to form a root hair. We assume that a hair growth promoter (HGP) is upregulated in root‐hair‐forming cells by a trichoblast‐specific component. Once established, HGP production is self‐enhancing. The autocatalytic regulation of HGP is antagonized by an HGP‐produced hair growth inhibitor (HGI). HGI is exported from trichoblasts and diffuses to neighboring cells, where it inhibits further HGP production and promotes the non‐hair cell fate. Under conditions of phosphate deficiency, we hypothesise that HGP production is increased and HGI diffusion rate is reduced, leading to a position‐independent formation of extra root hairs. BioEssays 30:75–81, 2008. © 2007 Wiley Periodicals, Inc. (shrink)

Recent studies support a model in which the progeny of SOX9+ epithelial progenitors at the distal tip of lung branches undergo cell allocation and differentiation sequentially along the distal‐to‐proximal axis. Concomitant with the elongation and ramification of lung branches, the descendants of the distal SOX9+ progenitors are distributed proximally, express SOX2, and differentiate into cell types in the conducting airways. Amid subsequent sacculation, the distal SOX9+ progenitors generate alveolar epithelial cells to form alveoli. Sequential cell allocation and (...) differentiation are integrated with the branching process to generate a functional branching organ. This review focuses on the roles of SOX9+ cells as precursors for new branches, as the source of various cell types in the conducting airways, and as progenitors of the alveolar epithelium. All of these processes are controlled by multiple signaling pathways. Many mouse mutants with defective lung branching contain underlying defects in one or more steps of cell allocation and differentiation of SOX9+ progenitors. This model provides a framework to understand the molecular basis of lung phenotypes and to elucidate the molecular mechanisms of lung patterning. It builds a foundation on which comparing and contrasting the mechanisms employed by different branching organs in diverse species can be made. (shrink)

The specification of specific and often unique fates to individual cells as a function of their position within a developing organism is a fundamental process during the development of multicellular organisms. The development of the Drosophila embryonic central nervous system serves as an excellent model system in which to clarify the developmental mechanisms that link pattern formation to cell-type specification. The Drosophila embryonic central nervous system develops from a set of neural stem cells termed neuroblasts. Neuroblasts arise from the (...) ectoderm in an invariant pattern, and each neuroblast acquires a unique fate based on its position within this pattern. Two groups of genes recently have been demonstrated to govern the individual fate specification of neuroblasts. One group, the segment polarity genes, enables neuroblasts that develop in different anteroposterior positions to acquire different fates. The second group, referred to as the columnar genes, ensures that neuroblasts that develop in different dorsoventral domains assume different fates. When integrated, the activities of the segment polarity and columnar genes create a Cartesian coordinate system that bestows unique fates to individual neuroblasts as a function of their position of formation within the ectoderm. BioEssays 1999;21:922–931. © 1999 John Wiley & Sons, Inc. (shrink)

Much of the current research in regenerative medicine concentrates on stem-cell therapy that exploits the regenerative capacities of stem cells when injected into different types of human tissues. Although new therapeutic paths have been opened up by induced pluripotent cells and human mesenchymal cells, the rate of success is still low and mainly due to the difficulties of managing cell proliferation and differentiation, giving rise to non-controlled stem cell differentiation that ultimately leads to cancer. Despite being still (...) far from becoming a reality, these studies highlight the role of physical and biological constraints (e.g., cues and morphogenetic fields) placed by tissue microenvironment on stem cell fate. This asks for a clarification of the coupling of stem cells and microenvironmental factors in regenerative medicine. We argue that extracellular matrix and stem cells have a causal reciprocal and asymmetric relationship in that the 3D organization and composition of the extracellular matrix establish a spatial, temporal, and mechanical control over the fate of stem cells, which enable them to interact and control (as well as be controlled by) the cellular components and soluble factors of microenvironment. Such an account clarifies the notions of stemness and stem cell regeneration consistently with that of microenvironment. (shrink)

CELL AND PSYCHE THE BIOLOGY OF PURPOSE By EDMUND W. SINNOTT. PREFACE TO THE TORCHBOOK EDITION: SINCE the publication of this little book, as the McNair Lectures at the University of North Carolina, the author has written two others, as well as a number of papers, on the same gen eral theme. Though these elaborate the argument a little further, the essence of it is in Cell and Psyche. This is admittedly a specula tion, but one based solidly (...) on biological fact. It has been regarded as rather visionary and metaphysical by some people, but others have been attracted to it by the suggestion it offers for a better understanding of the ancient problem of how mind and body are related to each other. This problem is of such paramount impor tance, not only for a knowledge of what man really is but for the construction of a satisfying life philosophy, that any light thrown on it should be welcome. The suggestion that man's physical life grows out of the basic goal-seeking and purposiveness found in all organic behavior and that this, in turn, is an aspect of the more general self - regulating and normative character evident in the development and activities of living organisms, is at least worth serious consideration. If we are to avoid a dualistic idea of man's nature and to construct a true monism that does not require the sacrifice of the significance of either mind or body, some such conception as this seems a rea sonable means of doing so. It is to be hoped that the wider distri bution now made possible for the present book may result in a more general consideration of this particular relationship between biol ogy and philosophy* E. W. S. CONTENTS: Introduction. i I. Organization, the Distinctive Character of All Life 15 II. Biological Organization and Psychological Activity 43 IIL Some Implications for Philosophy 75 Suggested Readings. 112 Index. 117. INTRODUCTION: IN THE CLAMOR and confusion of our times one fact grows ever clearer beliefs are important. One of the major problems with which men now are faced per haps, indeed, the most important one is the wide dis agreement which still exists in their fundamental philos ophies. What course a man will follow, or a nation, is set in no small measure by his basic creed, by what he really thinks about the true nature of a human being his personality, his freedom, his destiny, his relations to others and to the rest of the universe; by the judgments lie makes as to what qualities and courses of action are admirable and should command his allegiance. These are not academic questions merely. They arc ancient mys teries which long have troubled human hearts and seem today almost as far as ever from solution. The answer a ny* n gives to them is the most significant thing that one can know about him. We may be tempted to under estimate the importance of these inner directives and turn instead to outer influences, to economic and social factors, as more decisive for our actions. But when we look at what the philosophy of Marx has done to set one half the world against the other, at the basic divergence between the thinking of East and West, and at so many other differences in political and religious beliefs which now divide mankind, we can hardly doubt the profound practical import of men's philosophies. It is still true today that as a man thinketh in his heart, so is he. In the minds of men are the most fateful battles fought. Against those ideologies we condemn, force in the end will fail. If our opponents cannot be convinced, or their ideas reconci. (shrink)

Studies performed in absence of gravitational constraint show that a living system is unable to choose between two different phenotypes, thus leading cells to segregate into different, alternative stable states. This finding demonstrates that the genotype does not determine by itself the phenotype but requires additional, physical constraints to finalize cell differentiation. Constraints belong to two classes: holonomic (independent of the system's dynamical states, as being established by the space‐time geometry of the field) and non‐holonomic (modified during those biological (...) processes to which they contribute in shaping). This latter kind of “constraints”, in which dynamics works on the constraint to recreate them, have emerged as critical determinants of self‐organizing systems, by manifesting a “closure of constraints.” Overall, the constraints act by harnessing the “randomness” represented by the simultaneous presence of equiprobable events restraining the system within one attractor. These results cast doubt on the mainstream scientific concept and call for a better understanding of causation in cell biology. (shrink)

The stereotyped pattern of cell commitments during leech embryogenesis is described. The nature of cell commitments during segmentation differs significantly between leech and fruit fly. Despite the constancy of cell fate assignments in normal development, ablation experiments show that cell interactions are essential in setting some of these commitments. Interacting cells follow a positionally determined hierarchy of fate choices. For other cells, which appear to have fates fixed from birth, the possibility of determinative interactions (...) between mother and daughter cells is discussed. (shrink)

Glial cells play a central role in the development and function of complex nervous systems. Drosophila is an excellent model organism for the study of mechanisms underlying neural development, and recent attention has been focused on the differentiation and function of glial cells. We now have a nearly complete description of glial cell organization in the embryo, which enables a systematic genetic analysis of glial cell development. Most glia arise from neural stem cells that originate in the neurogenic (...) ectoderm. The bifurcation of glial and neuronal fates is under the control of the glial promoting factor glial cells missing. Differentiation is propagated through the regulation of several transcription factors. Genes have been discovered affecting the terminal differentiation of glia, including the promotion glial–neuronal interactions and the formation of the blood–nerve barrier. Other roles of glia are being explored, including their requirement for axon guidance, neuronal survival, and signaling. BioEssays 23:877–887, 2001. © 2001 John Wiley & Sons, Inc. (shrink)

Establishment of cell lineage identity from multipotent progenitors is controlled by cooperative actions of lineage‐specific and stably expressed transcription factors, combined with input from environmental signals. Lineage‐specific master transcription factors activate and repress gene expression by recruiting consistently expressed transcription factors and chromatin modifiers to their target loci. Recent technical advances in genome‐wide and multi‐omics analysis have shed light on unexpected mechanisms that underlie more complicated actions of transcription factors in cell fate decisions. In this review, we (...) discuss functional dynamics of stably expressed and continuously required factors, Notch and Runx family members, throughout developmental stages of early T cell development in the thymus. Pre‐ and post‐commitment stage‐specific transcription factors induce dynamic redeployment of Notch and Runx binding genomic regions. Thus, together with stage‐specific transcription factors, shared transcription factors across distinct developmental stages regulate acquisition of T lineage identity. (shrink)