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Results for “fate restriction”

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PubMed2002

Hematopoietic stem cells and their precursors: developmental diversity and lineage relationships.

Within the context of the developing embryo, restrictions in cell lineage potential occur through cell-cell interactions and signaling molecules, leading to changes in genetic programs and to the emergence of disparate tissues containing functionally distinct cell types including somatic stem cells. Tissue maintenance in the adult is thought to occur through specific stem cells, and in the case of the hematopoietic system, through hematopoietic stem cells (HSCs). These cells arise in midgestation within the region of the embryo containing the dorsal aorta, gonads, and mesonephros (AGM) and are thought to maintain a distinct hematopoietic lineage-restricted fate. However, recent transplantation experiments suggest that within the adult, HSCs previously thought to be restricted can, under certain circumstances, display unexpected lineage potentials. With these surprising and controversial results, it is becoming apparent that a better understanding of the developmental processes, molecular programs and lineage relationships leading to the emergence of adult stem cells will provide insight into the incremental steps involved in lineage determination, and perhaps possibilities for the manipulated differentiation of stem cells. The most widely studied, accessible stem cell and cellular differentiation hierarchy is that of the hematopoietic system. With the issue of stem cell potential in the forefront, the focus of this review is on the development of the hematopoietic system: how HSCs arise in the embryo, the lineage relationships of hematopoietic cells as they are generated, and the identification of precursor cells fated to the hematopoietic lineage throughout ontogeny.

Animals↗

PubMed2005

Cortical neuron specification: it has its time and place.

Cortical neurogenesis is a highly stereotyped process in which progenitor cells generate neurons destined for specific cortical layers depending on the timing of cell cycle exit. Previous work has shown that during corticogenesis, progenitors become progressively restricted in their developmental potential. Recent work has uncovered some of the intrinsic mechanisms that underlie this fate restriction. In addition to timing, new studies suggest that the location of cell cycle exit in the cortical germinal zone may also contribute to cortical neuron specification.

Animals↗

PubMed2005

Efficient differentiation and integration of lineage-restricted neural precursors in the traumatically injured adult cat spinal cord.

Several recent studies have shown that highly undifferentiated neural stem cells (NSCs) grafted into the intact or injured adult spinal cord of animal either remain undifferentiated or show fate restriction to a astrocytic lineage. This indicates that functionally diverse roles expected of cellular replacement cannot be performed by the transplantation of highly immature precursors; rather, more differentiated or appropriate mixtures of more restricted neural precursors may be important in replacement strategies. In this study, we investigated the ability of lineage-restricted neural progenitors derived from adult mouse periventricular subependymal zone (SEZ) to integrate and differentiate into the chronically injured adult spinal cord. To this end, NSCs were grown as adherent cultures followed by expansion in non-adhesive dishes. This allowed us to grow NSCs as colonies of restricted neural precursors, illustrated by NCAM, nestin, Sox-2, A2B5, and GFAP immunostaining. The mixture of lineage-restricted precursors was directly implanted into the chronically injured spinal cord of immunosuppressed cats. The fate of the cells was traced with GFP fluorescence and immunocytochemistry for neural markers such as beta-III-tubulin, GFAP, and Ng2. After four weeks, transplanted cells survived, giving rise to neurons and in addition to cells with an astrocytic phenotype. We conclude that a mixture of more restricted neural precursors may be better suited than highly immature NSCs for neural replacement strategies after central nervous system (CNS) injuries.

Animals↗

PubMed2006

Early hematopoietic lineage restrictions directed by Ikaros.

Ikaros is expressed in early hematopoietic progenitors and is required for lymphoid differentiation. In the absence of Ikaros, there is a lack of markers defining fate restriction along lympho-myeloid pathways, but it is unclear whether formation of specific progenitors or expression of their markers is affected. Here we use a reporter based on Ikaros regulatory elements to separate early progenitors in wild-type and Ikaros-null mice. We found previously undetected Ikaros-null lympho-myeloid progenitors lacking the receptor tyrosine kinase Flt3 that were capable of myeloid but not lymphoid differentiation. In contrast, lack of Ikaros in the common myeloid progenitor resulted in increased formation of erythro-megakaryocytes at the expense of myeloid progenitors. Using this approach, we identify previously unknown pivotal functions for Ikaros in distinct fate 'decisions' in the early hematopoietic hierarchy.

Animals↗

PubMed2002

Cell lineage analysis of the amphipod crustacean Parhyale hawaiensis reveals an early restriction of cell fates.

In the amphipod crustacean, Parhyale hawaiensis, the first few embryonic cleavages are total and generate a stereotypical arrangement of cells. In particular, at the eight-cell stage there are four macromeres and four micromeres, and each of these cells is uniquely identifiable. We describe our studies of the cell fate pattern of these eight blastomeres, and find that the eight clones resulting from these cells set up distinct cell lineages that differ in terms of proliferation, migration and cell fate. Remarkably, the cell fate of each blastomere is restricted to a single germ layer. The ectoderm originates from three of the macromeres, while the remaining macromere generates the visceral mesoderm. Two of the micromeres generate the somatic mesoderm, a third micromere generates the endoderm and the fourth micromere generates the germline. These findings demonstrate for the first time a total cleavage pattern in an arthropod which results in an invariant cell fate of the blastomeres, but notably, the cell lineage pattern of Parhyale reported shows no clear resemblance to those found in spiralians, nematodes or deuterostomes. Finally, the techniques we have developed for the analysis of Parhyale development suggest that this arthropod may be particularly useful for future functional analyses of crustacean development.

Animals↗

PubMed2001

Context-dependent regulation of fate decisions in multipotent progenitor cells of the peripheral nervous system.

A challenging problem in neural crest development is to understand how a migratory population of multipotent stem cells gives rise to a diverse array of differentiated cell types in the correct spatiotemporal manner. There is now ample evidence that this process involves the generation of postmigratory progenitor cells present in a variety of neural crest targets. When individual progenitors are challenged by instructive growth factors they are able to produce neural and non-neural cells, raising the question of how fate restrictions appropriate to a given embryonic location are regulated in multipotent postmigratory progenitor cells. Although some of the extracellular cues involved have been identified, it is likely that fate decisions in progenitor cells are controlled by the combinatorial action of multiple environmental signals. Moreover, cell type specificity is thought to be regulated by an interplay between extracellular and intracellular cues. We are just beginning to unravel some of the mechanisms that allow the context-dependent integration of cell-extrinsic and cell-intrinsic signals in multipotent progenitor cells.

Animals↗

PubMed2005

Step-wise specification of retinal stem cells during normal embryogenesis.

The specification of embryonic cells to produce the retina begins at early embryonic stages as a multi-step process that gradually restricts fate potentials. First, a subset of embryonic cells becomes competent to form retina by their lack of expression of endo-mesoderm-specifying genes. From these cells, a more restricted subset is biased to form retina by virtue of their close proximity to sources of bone morphogenetic protein antagonists during neural induction. During gastrulation, the definitive RSCs (retinal stem cells) are specified as the eye field by interactions with underlying mesoderm and the expression of a network of retina-specifying genes. As the eye field is transformed into the optic vesicle and optic cup, a heterogeneous population of RPCs (retinal progenitor cells) forms to give rise to the different domains of the retina: the optic stalk, retinal pigmented epithelium and neural retina. Further diversity of RPCs appears to occur under the influences of cell-cell interactions, cytokines and combinations of regulatory genes, leading to the differentiation of a multitude of different retinal cell types. This review examines what is known about each sequential step in retinal specification during normal vertebrate development, and how that knowledge will be important to understand how RSCs might be manipulated for regenerative therapies to treat retinal diseases.

Animals↗

PubMed1998

Identification of Miranda protein domains regulating asymmetric cortical localization, cargo binding, and cortical release.

An important question in cellular and developmental biology is how a cell divides to produce daughter cells with different fates. Drosophila neuroblasts are a model system for studying asymmetric cell division: at each division, neuroblasts retain stem cell-like features, whereas their sibling ganglion mother cell (GMC) has a more restricted fate. Establishing neuroblast/GMC differences involves the asymmetric localization of proteins (Inscuteable, Miranda, Prospero, and Staufen) and RNA (prospero). All of these factors are apically localized during interphase, and all except Inscuteable move to the basal cortex at mitosis prior to being partitioned solely into the GMC. In this study, we show that Miranda is colocalized with Staufen and Prospero in neuroblasts, and is required for the asymmetric cortical localization of both proteins. Analysis of miranda mutants reveals three functional domains within the Miranda protein: (1) an N-terminal domain (1-290 aa) sufficient for association of Miranda with the cell cortex and basal localization in mitotic neuroblasts; (2) a central domain (446-727 aa) necessary for apical localization in interphase neuroblasts as well as for "cargo binding" of Prospero, Staufen, and prospero mRNA; and (3) a C-terminal domain (727-830 aa) necessary for the timely degradation of Miranda and release of its cargo from the cortex of the newborn GMC. In addition, Miranda is asymmetrically localized in epithelial cells that lack Inscuteable and divide symmetrically; thus the mechanism regulating Miranda localization is common to epithelial cells and neuroblasts, and Inscuteable is not an obligate component. Finally, we define a C-terminal domain of Staufen sufficient for Miranda-dependent cortical localization in neuroblasts.

Amino Acid Sequence↗

PubMed2000

Intrinsic bias and lineage restriction in the phenotype determination of dopamine and neuropeptide Y amacrine cells.

Blastomere lineages are differentially biased to produce different neurotransmitter subtypes of amacrine cells (Huang and Moody, 1995, 1997,). To elucidate when this bias is acquired, we examined amacrine lineages at different early developmental times. Our experiments demonstrate that the bias to express dopamine and neuropeptide Y amacrine fates involves several steps before the formation of the definitive optic cup. At cleavage stages, a retinal progenitor that contributes large numbers of cells is already biased to produce its normal repertoire of dopamine amacrine cells, as revealed by transplantation to a new location, whereas the amacrine fate of a progenitor that contributes fewer cells is modified by its new position. At neural plate stages, not all retinal progenitors are multipotent. Nearly one-half populate only the inner nuclear layer and are enriched in amacrine cells. During early optic vesicle stages, an appropriate mitotic tree is required for dopamine and neuropeptide Y, but not serotonin, amacrine cell clusters to form. Thus, the acquisition of amacrine fate bias involves intrinsic maternal factors at cleavage, fate restriction in the neural plate, and specified mitotic patterns in the optic vesicle. At each of these steps only a subset of the embryonic retinal progenitors contributing to amacrine subtypes is biased; the remaining progenitors maintain multipotency. Thus, from the earliest embryonic stages, progenitors of the retina are a dynamic mosaic. This is the first experimental demonstration of amacrine fate decisions that occur during early embryonic periods in advance of the events described in the later, committed retina.

Animals↗

PubMedDate not supplied

Stem cells in regenerative biology and medicine.

Embryonic stem cells of the mammalian blastocyst give rise to all the tissue lineages that begin to emerge at gastrulation. They are pluripotent cells and can be propagated in vitro without loss of pluripotency. Many adult tissues harbor cells that do not complete their differentiation program. These cells serve as self-renewing stem cells whose normal fate is to regenerate site-specific tissue, in response to either physiological cell turnover or damage inflicted by injury or disease. Neural, muscle, and bone marrow stem cells possess developmental potency far greater than their normal lineage-restricted fate. The understanding of the biology of stem cells is leading us into an era of regenerative medicine. The growth potential and pluripotency of embryonic stem cells and the developmental plasticity of adult stem cells, particularly those of bone marrow, make them potentially useful for replacing tissues, via transplantation or construction of bioartificial tissues, that either do not regenerate naturally or are damaged beyond their natural capability for regeneration. In addition to these two ways of replacing tissue, a third strategy of regenerative medicine is to stimulate regeneration in vivo from resident stem cells. Before these approaches become clinical reality, however, a number of basic research issues must be resolved, including the revision of our concept of a regeneration-competent cell.

Bone Marrow Cells↗

PubMed2002

Cell-intrinsic and cell-extrinsic cues regulating lineage decisions in multipotent neural crest-derived progenitor cells.

Multipotent stem cells must generate various differentiated cell types in correct number and sequence during neural development. In the peripheral nervous system (PNS), this involves the formation of postmigratory progenitor cell types which maintain multipotency and are able to give rise to neural and non-neural cells in response to instructive growth factors. We propose that fate restrictions in such progenitor cells are controlled by the combinatorial interaction of different extracellular signals, including community effects in response to both neurogenic and gliogenic factors. In addition, distinct progenitor cell types display intrinsic differences which modulate their response to the extracellular environment. Thus, a progenitor cell is apparently able to integrate multiple intrinsic and extrinsic cues and thereby to choose fates appropriate for its location. Fate analysis of genetically modified progenitor cells will help to identify the molecules involved. This approach appears promising given the identification of multipotent progenitor cells from the mouse PNS and the availability of genetics in the mouse system.

Animals↗

PubMed2003

Transdifferentiation--fact or artifact.

Normal development appears to involve a progressive restriction in developmental potential. However, recent evidence suggests that this progressive restriction is not irreversible and can be altered to reveal novel phenotypic potentials of stem, progenitor, and even differentiated cells. While some of these results can be explained by the presence of contaminating cell populations, persistence of pluripotent stem cells, cell fusion, etc., several examples exist that are difficult to explain as anything other than "true transdifferentiation" and/or dedifferentiation. These examples of transdifferentiation are best explained by understanding how the normal process of progressive cell fate restriction occurs during development. We suggest that subversion of epigenetic controls regulating cell type specific gene expression likely underlies the process of transdifferentiation and it may be possible to identify specific factors to control the transdifferentiation process. We predict, however, that transdifferentiation will not be reliable or reproducible and will probably require complex manipulations.

Animals↗

PubMed1999

P0 and PMP22 mark a multipotent neural crest-derived cell type that displays community effects in response to TGF-beta family factors.

Protein zero (P0) and peripheral myelin protein 22 (PMP22) are most prominently expressed by myelinating Schwann cells as components of compact myelin of the peripheral nervous system (PNS), and mutants affecting P0 and PMP22 show severe defects in myelination. Recent expression studies suggest a role of P0 and PMP22 not only in myelination but also during embryonic development. Here we show that, in dorsal root ganglia (DRG) and differentiated neural crest cultures, P0 is expressed in the glial lineage whereas PMP22 is also detectable in neurons. In addition, however, P0 and PMP22 are both expressed in a multipotent cell type isolated from early DRG. Like neural crest stem cells (NCSCs), this P0/PMP22-positive cell gives rise to glia, neurons and smooth-muscle-like cells in response to instructive extracellular cues. In cultures of differentiating neural crest, a similar multipotent cell type can be identified in which expression of P0 and PMP22 precedes the appearance of neural differentiation markers. Intriguingly, this P0/PMP22-positive progenitor exhibits fate restrictions dependent on the cellular context in which it is exposed to environmental signals. While single P0/PMP22-positive progenitor cells can generate smooth muscle in response to factors of the TGF-(beta) family, communities of P0/PMP22-positive cells interpret TGF-(beta) factors differently and produce neurons or undergo increased cell death instead of generating smooth-muscle-like cells. Our data are consistent with a model in which cellular association of postmigratory multipotent progenitors might be involved in the suppression of a non-neural fate in forming peripheral ganglia.

Animals↗

PubMed1998

Additional vegetative growth in maize reflects expansion of fates in preexisting tissue, not additional divisions by apical initials.

The maize shoot is usually determinate: the apical meristem produces a fixed number of vegetative nodes before it switches to tassel development. Culturing maize meristems, however, delays their determinacy. Cultured meristems may form up to twice the usual number of vegetative nodes. Clonal analysis of the "extra" vegetative nodes reveals that these nodes are the product of conversion, roughly equivalent to a homoeotic transformation, of tissue that otherwise would form the base of the tassel. Altered activity of the apical initials does not generate the extra vegetative growth. The conserved, stereotypical activity of the apical initials even in the face of radically prolonged vegetative growth suggests that apical initials in this annual grass may acquire a highly restricted fate (presporogenous tissue) early in embryogenesis.

Cell Count↗

PubMed1998

Wing development and specification of dorsal cell fates in the absence of apterous in Drosophila.

The development and patterning of the Drosophila wing relies on interactions between cell populations that have the anteroposterior (AP) axis and dorsoventral (DV) axis of the wing imaginal disc as frames of reference [1-3]. Each of these cell populations gives rise to a compartment - a group of cells that have their fates restricted by cell lineage - within which cells acquire specific identities through the expression of 'selector' genes [1,2,4]. The genes engrailed (en) and invected (inv), for example, label cells in the posterior compartment and mediate a set of cell interactions that direct the patterning and growth of the wing along the AP axis [1,2,4]. A similar situation has been proposed to exist across the DV axis, along with apterous (ap) as a dorsal selector gene [5], mediating cell interactions by regulating the expression of Serrate (Ser) [6] [7] and fringe (fng) [8]. In ap mutants, the wing is lost [5] [9], and here we report that this phenotype can be rescued by ectopic expression of either Ser or fng and that, surprisingly, the resulting wings have both dorsal and ventral cell fates.

Animals↗

PubMed2006

The eventful somite: patterning, fate determination and cell division in the somite.

The segmental somites not only determine the vertebrate body plan, but also represent turntables of cell fates. The somite is initially naive in terms of its fate restriction as shown by grafting and rotation experiments whereby ectopically grafted or rotated tissue of newly formed somites yielded the same pattern of normal derivatives. Somitic derivatives are determined by local signalling between adjacent embryonic tissues, in particular the neural tube, notochord, surface ectoderm and the somitic compartments themselves. The correct spatio-temporal specification of the deriving tissues, skeletal muscle, cartilage, endothelia and connective tissue is achieved by a sequence of morphogenetic changes of the paraxial mesoderm, eventually leading to the three transitory somitic compartments: dermomyotome, myotome and sclerotome. These structures are specified along a double gradient from dorsal to ventral and from medial to lateral. The establishment and controlled disruption of the epithelial state of the somitic compartments are crucial for development. In this article, we give a synopsis of some of the most important signalling events involved in somite patterning and cell fate decisions. Particular emphasis has been laid on the issue of epithelio-mesenchymal transition and different types of cell division in the somite.

Animals↗

PubMed2002

Suppression of the melanogenic potential of migrating neural crest-derived cells by the branchial arches.

The development of melanocytes from neural crest-derived precursors that migrate along the dorsolateral pathway has been attributed to the selection of this route by cells that are fate-restricted to the melanocyte lineage. Alternatively, melanocytes could arise from nonspecified cells that develop in response to signals encountered while these cells migrate, or at their final destinations. In most animals, the bowel, which is colonized by crest-derived cells that migrate through the caudal branchial arches, contains no melanocytes; however, the enteric microenvironment does not prevent melanocytes from developing from crest-derived precursors placed experimentally into the bowel wall. To test the hypothesis that the branchial arches remove the melanogenic potential from the crest-derived population that colonizes the gut, the Silky fowl (in which the viscera are pigmented) was studied. Sources of crest included Silky fowl and quail vagal and truncal neural folds/tubes, which were cultured or explanted to chorioallantoic membranes alone or together with branchial arches or limb buds from Silky fowl, White Leghorn, or quail embryos. Crest and mesenchyme-derived cells were distinguished by using the quail nuclear marker. Melanocytes developed from Silky fowl and quail crest-derived cells. Melanocyte development from both sources was inhibited by quail and White Leghorn branchial arches (and limb buds), but melanocyte development was unaffected by branchial arch (and limb buds) from Silky fowl. These observations suggest that a factor(s) that is normally expressed in the branchial arches, and is lacking in animals with the Silky mutation, prevents cells with a melanogenic potential from colonizing the bowel.

Animals↗

PubMed2004

Cardiac neural crest stem cells.

Whereas the heart itself is of mesodermal origin, components of the cardiac outflow tract are formed by the neural crest, an ectodermal derivative that gives rise to the peripheral nervous system, endocrine cells, melanocytes of the skin and internal organs, and connective tissue, bone, and cartilage of the face and ventral neck, among other tissues. Cardiac neural crest cells participate in the septation of the cardiac outflow tract into aorta and pulmonary artery. The migratory cardiac neural crest consists of stem cells, fate-restricted cells, and cells that are committed to the smooth muscle cell lineage. During their migration within the posterior branchial arches, the developmental potentials of pluripotent neural crest cells become restricted. Conversely, neural crest stem cells persist at many locations, including in the cardiac outflow tract. Many aspects of neural crest cell differentiation are driven by growth factor action. Neurotrophin-3 (NT-3) and its preferred receptor, TrkC, play important roles not only in nervous system development and function, but also in cardiac development as deletion of these genes causes outflow tract malformations. In vitro clonal analysis has shown a premature commitment of cardiac neural crest stem cells in TrkC null mice and a perturbed morphology of the endothelial tube. Norepinephrine transporter (NET) function promotes the differentiation of neural crest stem cells into noradrenergic neurons. Surprisingly, many diverse nonneuronal embryonic tissues, in particular in the cardiovascular system, express NET also. It will be of interest to determine whether norepinephrine transport plays a role also in cardiovascular development.

Animals↗