The origin of Metazoa: a transition from temporal to spatial cell differentiation

For over a century, Haeckel's Gastraea theory remained a dominant theory to explain the origin of multicellular animals. According to this theory, the animal ancestor was a blastula‐like colony of uniform cells that gradually evolved cell differentiation. Today, however, genes that typically control metazoan development, cell differentiation, cell‐to‐cell adhesion, and cell‐to‐matrix adhesion are found in various unicellular relatives of the Metazoa, which suggests the origin of the genetic programs of cell differentiation and adhesion in the root of the Opisthokonta. Multicellular stages occurring in the complex life cycles of opisthokont protists (mesomycetozoeans and choanoflagellates) never resemble a blastula. Here, we discuss a more realistic scenario of transition to multicellularity through integration of pre‐existing transient cell types into the body of an early metazoon, which possessed a complex life cycle with a differentiated sedentary filter‐feeding trophic stage and a non‐feeding blastula‐like larva, the synzoospore. Choanoflagellates are considered as forms with secondarily simplified life cycles.     

Cell differentiation and morphogenesis in the colony-forming choanoflagellate Salpingoeca rosetta

It has been posited that animal development evolved from pre-existing mechanisms for regulating cell differentiation in the single celled and colonial ancestors of animals. Although the progenitors of animals cannot be studied directly, insights into their cell biology may be gleaned from comparisons between animals and their closest living relatives, the choanoflagellates. We report here on the life history, cell differentiation and intercellular interactions in the colony-forming choanoflagellate Salpingoeca rosetta. In response to diverse environmental cues, S. rosetta differentiates into at least five distinct cell types, including three solitary cell types (slow swimmers, fast swimmers, and thecate cells) and two colonial forms (rosettes and chains). Electron microscopy reveals that cells within colonies are held together by a combination of fine intercellular bridges, a shared extracellular matrix, and filopodia. In addition, we have discovered that the carbohydrate-binding protein wheat germ agglutinin specifically stains colonies and the slow swimmers from which they form, showing that molecular differentiation precedes multicellular development. Together, these results help establish S. rosetta as a model system for studying simple multicellularity in choanoflagellates and provide an experimental framework for investigating the origin of animal multicellularity and development.     

Origin of the phyla and cancer

Multicelled animals with specialized cells (metazoans) emerged shortly after rising oxygen levels in the seas permitted formation of collagen-family molecules. Certain unicells then formed 3-D clusters, some with disc- or ball-like shapes that happened to resemble blastulas. These became unstable beyond a certain size due to contrasting metabolic styles among their component cells. For whereas cells near their exteriors could employ oxygen respiration, cells closer to the oxygen-deprived interiors were obliged to rely on anaerobic metabolism (fermentation), a process that produces waste molecules that, if retained within cells, cause disproportionate cell growth. Unstable blastula-like forms would either disintegrate or reorganize along surfaces of relative weakness in a process that may be likened to gastrulation. Initial cell-differentiation depended on the quantity and diversity of retained fermentation products and on the pumping of molecules from cell to cell by the consequent electro-chemical gradients. In subsequent contexts, oxygen deprivation, fermentation, excess cell growth, and disintegration or reorganization of tissues produce cancer.     

Survival of the fittest: metabolic adaptations in cancer

Malignant transformation is often a multistep process characterized by an initial period of avascular growth. Rapid cell proliferation creates areas within the emerging preneoplastic lesion with limited diffusion of oxygen and nutrients. In this context, activation of oncogenes, loss of tumor suppressors as well as additional adaptive mechanisms drive a profound metabolic rewiring to overcome the environmental constraints. The emerging cells are in principle better suited to proliferate and survive in the hostile tumor microenvironment. Furthermore, some of the acquired metabolic traits impact their metastatic behavior and response to therapy. It is becoming increasingly clear that malignant cells are highly dependent on certain nutrients, an Achilles' heel of cancer and an opportunity for therapeutic intervention.     

Special symposium: In vitro plant recalcitrance loss of plant organogenic totipotency in the course of In vitro neoplastic progression

Summary The aptitude for organogenesis from normal hormone-dependent cultures very commonly decreases as the tissues are serially subcultured. The reasons for the loss of regenerative ability may vary under different circumstances: genetic variation in the cell population, epigenetic changes, disappearance of an organogenesis-promoting substance, etc. The same reasons may be evoked for the progressive and eventually irreversible loss of organogenic totipotency in the course of neoplastic progressions from hormone-independent tumors and hyperhydric teratomas to cancers. As in animal cells, plant cells at the end of a neoplastic progression have probably undergone several independent genetic accidents with cumulative effects. They indeed are characterized by atypical biochemical cycles from which they are apparently unable to escape. The metabolic changes are probably not the primary defects that cause cancer, rather they may allow the cells to survive. How these changes, namely an oxidative stress, affect organogenesis is not known. The literature focuses on somatic mutations and epigenetic changes that cause aberrant regulation of cell cycle genes and their machinery.     

The rate of free radical production as a determinant of the rate of aging: evidence from the comparative approach

The relationship of oxidative stress with maximum life span (MLSP) in different vertebrate species is reviewed. In all animal groups the endogenous levels of enzymatic and non-enzymatic antioxidants in tissues negatively correlate with MLSP and the most longevous animals studied in each group, pigeon or man, show the minimum levels of antioxidants. A possible evolutionary reason for this is that longevous animals produce oxygen radicals at a low rate. This has been analysed at the place where more than 90% of oxygen is consumed in the cell, the mitochondria. All available work agrees that, across species, the longer the life span, the lower the rate of mitochondrial oxygen radical production. This is true even in animal groups that do not conform to the rate of living theory of aging, such as birds. Birds have low rates of mitochondrial oxygen radical production, frequently due to a low free radical leak in their respiratory chain. Possibly the low rate of mitochondrial oxygen radical production of longevous species can decrease oxidative damage at targets important for aging (like mitochondrial DNA) that are situated near the places of free radical generation. A low rate of free radical production can contribute to a low aging rate both in animals that conform to the rate of living (metabolic) theory of aging and in animals with exceptional longevities, like birds and primates. Available research indicates there are at least two main characteristics of longevous species: a high rate of DNA repair together with a low rate of free radical production near DNA. Simultaneous consideration of these two characteristics can explain part of the quantitative differences in longevity between animal species. Accepted: 12 December 1997     

Immortality and the base of multicellular life: Lessons from cnidarian stem cells

Cnidarians are phylogenetically basal members of the animal kingdom (>600 million years old). Together with plants they share some remarkable features that cannot be found in higher animals. Cnidarians and plants exhibit an almost unlimited regeneration capacity and immortality. Immortality can be ascribed to the asexual mode of reproduction that requires cells with an unlimited self-renewal capacity. We propose that the basic properties of animal stem cells are tightly linked to this archaic mode of reproduction. The cnidarian stem cells can give rise to a number of differentiated cell types including neuronal and germ cells. The genomes of Hydra and Nematostella, representatives of two major cnidarian classes indicate a surprising complexity of both genomes, which is in the range of vertebrates. Recent work indicates that highly conserved signalling pathways control Hydra stem cell differentiation. Furthermore, the availability of genomic resources and novel technologies provide approaches to analyse these cells in vivo. Studies of stem cells in cnidarians will therefore open important insights into the basic mechanisms of stem cell biology. Their critical phylogenetic position at the base of the metazoan branch in the tree of life makes them an important link in unravelling the common mechanisms of stem cell biology between animals and plants.     

A food's-eye view of the transition from basal metazoans to bilaterians

Living things invariably consist of some kind of compartmentalizedredox chemistry. Signaling pathways mediated by oxidation andreduction thus derive from the nature of life itself. The roleof such redox or metabolic signaling broadened with major transitionsin the history of life. Prokaryotes often use redox signalsto deploy one or more variant electron carriers and associatedenzymes to better utilize environmental energy sources. Eukaryotestranscend the strong surface-to-volume constraints inherentin prokaryotic cells by moving chemiosmotic membranes internally.As a consequence, eukaryotic redox signaling is frequently betweenthese organelle membranes and the nucleus, thus potentiallyinvolving levels-of-selection synergies and antagonisms. Gradientsof oxygen and substrate in simple multicellular organisms similarlyassociated metabolic signaling with levels of selection, nowat the level of the cell and the organism. By allowing sequestrationof large amounts of food, the evolution of the animal mouthwas a pivotal event in metabolic signaling, leading to "multicellular"redox regulation. Because concentrated food resources may bepatchy in time and space, long-lived sedentary animals withmouths employ such metabolic signaling and phenotypic plasticityin ways that adapt them to the changing availability of food.Alternatively, if the mouth is coupled to a battery of sensoryequipment, the organism can actively seek out and sequesterpatches of food. In these early bilaterians, competition forfood resources may have favored rapid development with littlesubsequent plasticity and metabolic signaling. With rapid dispersaland colonization, such "assembly-line" animals could effectivelycompete for patchy resources. Limiting metabolic signaling,however, resulted in a cascade of seemingly unrelated changes.These changes derive from the effectiveness of metabolic signalingin policing variation at the cellular level. If the signalsan organism uses to control cellular replication are the sameas the signals a cell uses to control its own metabolism, thencells that ignore these signals and carry out selfish replicationwill pay a fitness cost in terms of inefficient metabolism.Bilaterians with limited metabolic signaling thus require othermechanisms to police cell-level variation. Bilaterian featuressuch as restricted somatic cell potency, a sequestered germline, and determinate growth should be viewed in this context.Bilaterian senescence evolved as a by-product of restrictedpotency of somatic cells, itself a mechanism of cell policingrequired by limited metabolic signaling.     

Did detoxification processes cause complex life to emerge?

Excess oxygen is toxic for many cells and cell function can be disrupted by calcium, even if present in small amounts. Cells avoid the toxic effects of these substances by excreting oxygen-rich or Ca-containing molecules. The origin of macroscopic multi-celled animals (metazoans) can be attributed to the excretion of oxygen-rich collagen molecules (or their precursors) at a time when the seas were for the first time both oxygenated and sufficiently loaded with phosphorus for the energy (ATP) requirements of sizable metazoans. With subsequent increase of Ca in the marine environment, hard parts of CaCO₃ were produced. Excretion of oxygen in combination with abundant phosphorus permitted phosphate biomineralization. In this view, the most informative biological development during the late Neoproterozoic was not the emergence of metazoans but the initial construction of viable tissues. When tissue integrity is lost, whether due to low oxygen, collagen failure, injury, chemical insult or other reasons, individual cells are released from tissue-constraints. To survive, they may then revert to unicellular life-styles that emphasize cellular proliferation and variation. When this occurs in metazoans, the result may be cancer.     

The role of DNA damage repair in aging of adult stem cells

DNA repair maintains genomic stability and the loss of DNA repair capacity results in genetic instability that may lead to a decline of cellular function. Adult stem cells are extremely important in the long-term maintenance of tissues throughout life. They regenerate and renew tissues in response to damage and replace senescent terminally differentiated cells that no longer function. Oxidative stress, toxic byproducts, reduced mitochondrial function and external exposures all damage DNA through base modification or mis-incorporation and result in DNA damage. As in most cells, this damage may limit the survival of the stem cell population affecting tissue regeneration and even longevity. This review examines the hypothesis that an age-related loss of DNA damage repair pathways poses a significant threat to stem cell survival and longevity. Normal stem cells appear to have strict control of gene expression and DNA replication whereas stem cells with loss of DNA repair may have altered patterns of proliferation, quiescence and differentiation. Furthermore, stem cells with loss of DNA repair may be susceptible to malignant transformation either directly or through the emergence of cancer-prone stem cells. Human diseases and animal models of loss of DNA repair provide longitudinal analysis of DNA repair processes in stem cell populations and may provide links to the physiology of aging.     

Sirtuins at the crossroads of stemness,aging, and cancer

Sirtuins are stress‐responsive proteins that direct various post‐translational modifications (PTMs) and as a result, are considered to be master regulators of several cellular processes. They are known to both extend lifespan and regulate spontaneous tumor development. As both aging and cancer are associated with altered stem cell function, the possibility that the involvement of sirtuins in these events is mediated by their roles in stem cells is worthy of investigation. Research to date suggests that the individual sirtuin family members can differentially regulate embryonic, hematopoietic as well as other adult stem cells in a tissue‐ and cell type‐specific context. Sirtuin‐driven regulation of both cell differentiation and signaling pathways previously involved in stem cell maintenance has been described where downstream effectors involved determine the biological outcome. Similarly, diverse roles have been reported in cancer stem cells (CSCs), depending on the tissue of origin. This review highlights the current knowledge which places sirtuins at the intersection of stem cells, aging, and cancer. By outlining the plethora of stem cell‐related roles for individual sirtuins in various contexts, our purpose was to provide an indication of their significance in relation to cancer and aging, as well as to generate a clearer picture of their therapeutic potential. Finally, we propose future directions which will contribute to the better understanding of sirtuins, thereby further unraveling the full repertoire of sirtuin functions in both normal stem cells and CSCs.     

Apoptotic pathways in adipose tissue

To treat the ever growing number of obese patients, reduction of adipocyte number by apoptosis may complement other therapeutic options. On the other hand in free fat grafts, apoptosis along with necrosis is responsible for long term volume reduction. To ensure successful soft tissue reconstruction it is mandatory to keep apoptosis on a low level in adipocytes, adipose-derived stromal cells and others cells of the fat graft. Apoptotic pathways have been sufficiently studied in various tissues, but the knowledge about apoptotic pathways in adipocytes is surprisingly scarce. Current knowledge about apoptotic pathways in adipose tissue is elaborately reflected in this review as well as the association of cancer with obesity. Possibilities to induce and reduce adipose tissue apoptosis in animal models are discussed as well as clinical implications of fat cell apoptosis. Mechanisms of apoptosis induction have been studied in animal models and suggest that a tight control of apoptosis induction is necessary because otherwise detrimental metabolic effects of fat mass loss will occur that may mimic lipodystrophic diseases. At present, targeted induction of adipocyte apoptosis appears to be of some concern related to increased blood lipid concentrations, ectopic lipid storage and other detrimental metabolic effects. Treatment of autologous adipocytes used for lipofilling procedures with appropriate substances may result in more satisfactory long-term outcomes as well as stimulation of stem cell differentiation in a strictly local manner.     

Independence among physiological traits suggests flexibility in the face of ecological demands on phenotypes

Phenotypic flexibility allows animals to adjust their physiology to diverse environmental conditions encountered over the year. Examining how these varying traits covary gives insights into potential constraints or freedoms that may shape evolutionary trajectories. In this study, we examined relationships among haematocrit, baseline corticosterone concentration, constitutive immune function and basal metabolic rate in red knot Calidris canutus islandica individuals subjected to experimentally manipulated temperature treatments over an entire annual cycle. If covariation among traits is constrained, we predict consistent covariation within and among individuals. We further predict consistent correlations between physiological and metabolic traits if constraints underlie species-level patterns found along the slow-fast pace-of-life continuum. We found no consistent correlations among haematocrit, baseline corticosterone concentration, immune function and basal metabolic rate either within or among individuals. This provides no evidence for constraints limiting relationships among these measures of the cardiovascular, endocrine, immune and metabolic systems in individual red knots. Rather, our data suggest that knots are free to adjust individual parts of their physiology independently. This makes good sense if one places the animal within its ecological context where different aspects of the environment might put different pressures on different aspects of physiology.     

The Precambrian emergence of animal life: a geobiological perspective

The earliest record of animals (Metazoa) consists of trace and body fossils restricted to the last 35 Myr of the Precambrian. It has been proposed that animals arose much earlier and underwent significant evolution as a cryptic fauna; however, the need for any unrecorded prelude of significant duration has been disputed. In this context, we consider recent published research on the nature and chronology of the earliest fossil record of metazoans and on the molecular‐based analysis that yielded older dates for the appearance of major animal groups. We review recent work on the climatic, geochemical, and ecological events that preceded animal fossils and consider their portent for metazoan evolution. We also discuss inferences about the physiology and gene content of the last common ancestor of animals and their closest unicellular relatives. We propose that the recorded Precambrian evolution of animals includes three intervals of advancement that begin with sponge‐grade organisms, and that any preceding cryptic fauna would be no more complex than sponges. The molecular data do not require that more complex animals appeared well before the recognized fossil record; nor, however, do they rule the possibility out, particularly if the interval of simpler metazoan ancestors lasted no more than about 100 or 200 Myr. The geological record of abrupt changes in climate, biogeochemistry, and phytoplankton diversity can be taken to be the result of changes in the carbon cycle triggered by the appearance and diversification of metazoans in an organic carbon‐rich ocean, but as yet no compelling evidence exists for this interpretation. By the end of this cryptic period, animals would already have possessed sophisticated systems of cell–cell signalling, adhesion, apoptosis, and segregated germ cells, possibly with a rudimentary body plan based on anterior–posterior organization. The controls on the timing and tempo of the earliest steps in metazoan evolution are unknown, but it seems likely that oxygen was a key factor in later diversification and increase in body size. We consider several recent scenarios describing how oxygen increased near the end of the Precambrian and propose that grazing and filter‐feeding animals depleted a marine reservoir of suspended organic matter, releasing a microbial ‘clamp’ on atmospheric oxygen.     

vasa and nanos expression patterns in a sea anemone and the evolution of bilaterian germ cell specification mechanisms

Most bilaterians specify primordial germ cells (PGCs) during early embryogenesis using either inherited cytoplasmic germ line determinants (preformation) or induction of germ cell fate through signaling pathways (epigenesis). However, data from nonbilaterian animals suggest that ancestral metazoans may have specified germ cells very differently from most extant bilaterians. Cnidarians and sponges have been reported to generate germ cells continuously throughout reproductive life, but previous studies on members of these basal phyla have not examined embryonic germ cell origin. To try to define the embryonic origin of PGCs in the sea anemone Nematostella vectensis, we examined the expression of members of the vasa and nanos gene families, which are critical genes in bilaterian germ cell specification and development. We found that vasa and nanos family genes are expressed not only in presumptive PGCs late in embryonic development, but also in multiple somatic cell types during early embryogenesis. These results suggest one way in which preformation in germ cell development might have evolved from the ancestral epigenetic mechanism that was probably used by a metazoan ancestor.