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PubMed2004

Smad7 alters cell fate decisions of human hematopoietic repopulating cells.

Intracellular Smad proteins mediate signal transduction of the transforming growth factor-beta (TGF-beta) superfamily that play pleiotropic roles in hematopoietic development, suggesting that intracellular Smad proteins may play key roles in hematopoietic regulation. Although inhibitory Smad7, which negatively regulates TGF-beta signaling, has been implicated in the development of mature hematopoietic cells, a role for Smad7 in regulating more primitive hematopoietic cells has yet to be examined. Here, Smad7 was overexpressed in primary human severe combined immunodeficient (SCID) repopulating cells (SRCs), representing a common myeloid/lymphoid precursor cell with the functional capacity to repopulate the bone marrow of nonobese diabetic (NOD)/SCID recipient mice. Retroviral transduction of Smad7 into human umbilical cord blood (CB)-SRCs caused a shift from lymphoid dominant engraftment toward increased myeloid contribution, and increased the myeloid-committed clonogenic progenitor frequency in reconstituted mice. Neither myeloid nor B-lymphoid lineage developmental stages were compromised by Smad7 overexpression, suggesting Smad7 regulates cell fate commitment decisions of myeloid/lymphoid precursors by augmenting myeloid differentiation at the expense of lymphoid commitment. In addition, global gene expression analysis using microarray was used to identify potential target genes regulated by Smad7 in primitive hematopoietic cells that may control this process. Our study demonstrates a novel and unexpected role for Smad7 in modulating the cell fate decisions of primary multipotent human repopulating cells and establishes a role for Smad7 in the development of primitive human hematopoietic cells.

Animals↗

PubMed2026

The DLX/Notch axis is necessary for spatiotemporal regulation of neural cell fate.

Neuronal-glial cell fate switch during forebrain development is highly regulated. DLX transcription factors are necessary for promoting GABAergic interneuron differentiation and migration but the mechanisms for concomitant repression of glial fate in neural progenitors remain elusive. Here, the DLX2 regulatory network dynamic in the developing ventral telencephalon is characterised using a multi-omic approach at single-cell resolution, including single-cell whole genome spatial transcriptomics. We identify a secondary proliferative zone in the ventral subventricular zone and spatiotemporal-context dependent Notch pathway repression by DLX2 in maintaining progenitor populations and facilitating neural differentiation. We find that DLX2 controls cell fate determination by directly repressing Notch signalling genes as well as glial fate-promoting transcription factors, thereby inhibiting early adoption of oligodendroglial differentiation during neurogenesis. Here, we show that temporal cell fate switch is mediated by DLX2 via a multilayer gene regulatory network, redefining current understanding of neuronal-glial cell specification mechanisms in the developing telencephalon.

Animals↗

PubMed2005

Differential expression of cell fate determinants in neurons and glial cells of adult mouse spinal cord after compression injury.

Cellular responses after spinal cord injury include activation of astrocytes, degeneration of neurons and oligodendrocytes, and reactions of the ependymal layer and meningeal cells. Because it has been suggested that tissue repair partially recapitulates morphogenesis, we have investigated the expression of several developmentally prominent molecules after spinal cord injury of adult mice where neurogenesis does not occur after injury. Cell fate determinants Numb, Notch-1, Shh and BMPs are abundantly expressed during development but mostly decline in the adult. In the present study, we investigated whether these genes are triggered by spinal cord injury as a sign of attempted recapitulation of development. Expression of Numb, Notch, Shh, BMP2/4 and Msx1/2 was analysed in the adult mouse spinal cord after compression injury by in situ hybridization up to 1 month after injury. The mRNA expression levels of Notch-1, Numb, Shh, BMP4 and Msx2 increased in the grey matter and/or white matter and in the ependyma rostral and caudal to the lesion site after injury. However, BMP2 and Msx1 were not up-regulated. Combining immunohistochemistry of cell type-specific markers with in situ hybridization we found that all the up-regulated genes were expressed in neurons. Moreover, Numb, BMP4 and Msx2 were also expressed by GFAP-positive astrocytes, while Shh was expressed by MBP-positive oligodendrocytes. In conclusion, the cell fate determinants Notch-1, Numb, Shh, BMP4 and Msx2 are expressed in neurons and/or glial cells after injury in a time-dependent manner, suggesting that these genes reflect to some extent an endogenous self-repair potential by recapitulating some features of development.

Animals↗

PubMed1983

The lin-12 locus specifies cell fates in Caenorhabditis elegans.

We describe two classes of mutations in the lin-12 locus of the nematode Caenorhabditis elegans. Ten semidominant mutations (lin-12[d]) appear to elevate the level of lin-12 activity. Thirty-two recessive alleles (lin-12[0]), including two amber mutations, appear to eliminate gene activity. The lin-12(d) and lin-12(0) mutations result in reciprocal homeotic transformations in the fates of defined cells in several different tissues. Gene dosage studies suggest that a high level of lin-12 activity specifies one cell fate and a low level specifies an alternative fate. Temperature-shift experiments indicate that lin-12 acts at the time cell fate is determined in wild type. We propose that lin-12 functions as a binary switch to control decisions between alternative cell fates during C. elegans development.

Alleles↗

PubMed1993

tramtrack is a transcriptional repressor required for cell fate determination in the Drosophila eye.

Cell fate determination in the Drosophila eye is mediated by inductive events between neighboring cells in the eye imaginal disc. These inductive signals lead to differential gene expression necessary for the elaboration of different cell types in the compound eye. Several putative transcription factors have been identified previously that may be required for expression of genes that specify cell fate in the compound eye. Repression of inappropriate gene expression may be as important as transcriptional activation in the determination of cell fate. We report the identification of a mutation in the Drosophila tramtrack (ttk) locus that is required for cell fate determination in the compound eye. ttk is expressed as two proteins, p69 and p88, shown previously to bind to the regulatory regions of several segmentation genes. In ttk1, an allele missing the mRNA encoding p88, many ommatidia contained supernumerary R7 cells and decreased numbers of R1-R6 cells. ttk1e11, which appears to disrupt both Ttk proteins, was characterized by early embryonic arrest as well as transformation of ommatidial cells into nonommatidial cell types in mosaic flies. Consistent with previous proposals that the Ttk proteins are transcriptional repressors of segmentation genes, we detected ectopic or increased expression of the segment polarity gene engrailed in several ttk1 larval tissues. We propose that p69 is required to repress expression of genes that are incompatible with development of photoreceptor cell fates, whereas p88 appears to be required to repress genes that promote the R7 cell fate.

Alternative Splicing↗

PubMed2025

Generative model for the first cell fate bifurcation in mammalian development.

The first cell fate bifurcation in mammalian development directs cells toward either the trophectoderm (TE) or inner cell mass (ICM) compartments in pre-implantation embryos. This decision is regulated by the subcellular localization of a transcriptional co-activator YAP and takes place over several progressively asynchronous cleavage divisions. As a result of this asynchrony and variable arrangement of blastomeres, reconstructing the dynamics of the TE/ICM cell specification from fixed embryos is extremely challenging. To address this, we developed a live-imaging approach and applied it to measure pairwise dynamics of nuclear YAP and its direct target genes, CDX2 and SOX2, which are key transcription factors of the TE and ICM, respectively. Using these datasets, we constructed a generative model of the first cell fate bifurcation, which reveals the time-dependent statistics of the TE and ICM cell allocation. In addition to making testable predictions for the joint dynamics of the full YAP/CDX2/SOX2 motif, the model revealed the stochastic nature of the induction timing of the key cell fate determinants and identified the features of YAP dynamics that are necessary or sufficient for this induction. Notably, temporal heterogeneity was particularly prominent for SOX2 expression among ICM cells. As heterogeneities within the ICM have been linked to the initiation of the second cell fate decision in the embryo, understanding the origins of this variability is of key significance. The presented approach reveals the dynamics of the first cell fate choice and lays the groundwork for dissecting the next cell fate decisions in mouse development.

Animals↗

PubMed2003

Specification of cell fates within the salivary gland primordium.

The Drosophila salivary gland is a simple tubular organ derived from a contiguous epithelial primordium, which is established by the activities of the homeodomain-containing proteins Sex combs reduced (SCR), Extradenticle (EXD), and Homothorax (HTH). EGF signaling along the ventral midline specifies the salivary duct fate for cells in the center of the primordium, while cells farther away from the source of EGF signal adopt a secretory cell fate. EGF signaling works, at least in part, by repressing expression of secretory cell genes in the duct primordium, including fork head (fkh), which encodes a winged-helix transcription factor. FKH, in turn, represses trachealess (trh), a duct-specific gene initially expressed throughout the salivary gland primordium. trh encodes a basic helix-loop-helix PAS-domain containing transcription factor that has been proposed to specify the salivary duct fate. In conflict with this model, we find that three genes, dead ringer (dri), Serrate (Ser), and trh itself, are expressed in the duct independently of trh. Expression of all three duct genes is repressed in the secretory cells by FKH. We also show that SER in the duct cells signals to the adjacent secretory cells to specify a third cell type, the imaginal ring cells. Thus, localized EGF- and Notch-signaling transform a uniform epithelial sheet into three distinct cell types. In addition, Ser directs formation of actin rings in the salivary duct.

Animals↗

PubMed2006

Human mesenchymal stem cells signals regulate neural stem cell fate.

Neural stem cells (NSCs) differentiate into neurons, astrocytes and oligodendrocytes depending on their location within the central nervous system (CNS). The cellular and molecular cues mediating end-stage cell fate choices are not completely understood. The retention of multipotent NSCs in the adult CNS raises the possibility that selective recruitment of their progeny to specific lineages may facilitate repair in a spectrum of neuropathological conditions. Previous studies suggest that adult human bone marrow derived mesenchymal stem cells (hMSCs) improve functional outcome after a wide range of CNS insults, probably through their trophic influence. In the context of such trophic activity, here we demonstrate that hMSCs in culture provide humoral signals that selectively promote the genesis of neurons and oligodendrocytes from NSCs. Cell-cell contacts were less effective and the proportion of hMSCs that could be induced to express neural characteristics was very small. We propose that the selective promotion of neuronal and oligodendroglial fates in neural stem cell progeny is responsible for the ability of MSCs to enhance recovery after a wide range of CNS injuries.

Animals↗

PubMed2004

Vacuolar H+-translocating inorganic pyrophosphatase (Vpp1) marks partial aleurone cell fate in cereal endosperm development.

Cereal endosperm is a model system for cell fate determination in plants. In wild-type plants the outermost endosperm cells adopt aleurone cell fate, while all underlying cells display starchy endosperm cell fate. Mutant analysis showed that cell fate is determined by position rather than lineage. To further characterise the precise cell fate of the outermost cells, we performed a differential screen and isolated the novel marker gene Vpp1 . It encodes a vacuolar H+-translocating inorganic pyrophosphatase (V-PPase) and is mainly expressed in kernels, leaves and tassels. In kernels, its expression is restricted to the aleurone layer with the maximum of expression shifting from the adaxial to the abaxial side during early stages. Together with three other marker genes Vpp1 was then used to analyse the cell fate of the outermost cells in Dap3 , Dap7 , cr4 and dek1 mutants, all of which have aberrant aleurone layers. In the Dap3 and Dap7 mutants the Vpp1 and Ltp2 markers but not the A1 and Zein markers were expressed in patches without aleurone indicating that the outermost cells had some but not all features of aleurone cells and did not simply adopt starchy endosperm cell fate. A similar result was obtained in the cr4 mutant, although Ltp2 expression was less generalised. In other Dap7 patches characterised by multiple aleurone-like cell layers the expression of Vpp1 and Ltp2 confirmed the aleurone cell fate of the cells in the additional cell layers. The analysis of dek1 mutants confirmed the starchy endosperm cell fate of the majority but not all outermost cells. Based on these data we propose a model suggesting a stepwise commitment to aleurone cell fate. Sequential steps are marked by the expression of Vpp1 , the expression of Ltp2 , the acquisition of a regular shape and thick walls and finally pigmentation coupled with A1 expression.

Cell Lineage↗

PubMed2005

The effect of ethanol on cell fate determination of neural stem cells.

BACKGROUND: Recent studies have described the possible relevance of impaired neural stem cell (NSC) functions to the pathophysiology of psychiatric disorders, including alcoholism. However, relatively little is known about ethanol's effects on the determination of cell fate in NSCs. In this study, we investigated the effect of ethanol on neuronal and glial differentiation of NSCs. METHODS: Under neuron-inductive culture conditions, NSCs were induced to differentiate and exposed to ethanol for 96 hr. Immunocytochemistry with cell-type-specific markers was performed (microtubule-associated protein 2 (MAP2) for neurons, glial fibrillary acidic protein (GFAP) for astrocytes and O4 for oligodendrocytes). The cells positive to MAP2, GFAP or O4 were counted, and the number of MAP2-positive cells was quantified by enzyme-linked immunosorbent assay (ELISA) following immunostaining with anti-MAP2 (MAP2-ELISA). The alteration of MAP2, GFAP or myelin basic protein (MBP, a marker for oligodendrocytes) expression was evaluated by Western blot analysis. RESULTS: Ethanol exposure increased astrocytic and oligodendrocytic differentiation with a statistically significant difference at 100 mM, while 25 to 100 mM ethanol reduced neuronal differentiation without affecting the viability of NSCs. The enhanced expression of glial markers was revealed by Western blot analysis for GFAP or MBP. CONCLUSIONS: Glial cells are known to increase in response to various kinds of insults to the central nervous system. It is possible that the increase of astrocytes and oligodendrocytes after ethanol exposure is a compensatory mechanism to repair the impaired neural network by promoting neurite outgrowth and increasing newly generated neurons.

Animals↗

PubMed1999

Cell-fate decisions in early T cell development: regulation by cytokine receptors and the pre-TCR.

During lymphocyte development, cell-fate decisions are determined by a myriad of signals produced by the micro- environment of the thymus and the bone marrow. These yet to be fully defined developmental cues regulate stage-specific gene expression, and the extraordinarily well-characterized stages of T and B cell development have provided attractive model systems for studying regulation of cellular differentiation. In particular, studies on the contribution of both antigen receptors and cytokine receptors to lymphoid development have illuminated essential signalling pathways in early T and B cells. Here, we review investigations supporting an obligatory role for the IL-7 receptor pathway in early T cell development. IL-7 is produced by both thymus and bone marrow stromal cells, and its potential contribution to survival, differentiation and proliferation of pro-T cells is discussed. We also address the contribution of the pre-T cell receptor (pre-TCR) to differentiation past the pro-T cell stage, and recent advances in deciphering the composition and function of the pre-TCR complex are discussed. Finally, we suggest future directions in this field that may serve to reveal whether and how signals initiated by the cytokine receptors and pre-TCR may intersect, and to define which down-stream molecular events are regulated by these receptors.

Animals↗

PubMed2006

Endothelial and hematopoietic cell fate of human embryonic stem cells.

The endothelial cells, lining the inside of blood vessels, and the blood-forming hematopoietic cells play crucial roles in vasculogenesis. The establishment of human embryonic stem cells (hESCs) provides a unique tool to study the early development of endothelial and hematopoietic cells, opening new avenues of research to explore organ vascularization and regeneration. The current study demonstrates that a population of intermediate-stage precursors, which possesses primitive endothelial properties during hESC differentiation, is capable of giving rise to endothelial and hematopoietic cells. Single cell analysis reveals that these primitive endothelial-like precursors contain rare bipotent cells with hemangioblast properties, responsible for both endothelial and hematopoietic cell fates. These findings will facilitate the further study of cellular commitment, lineage restriction, and terminal differentiation of endothelial and hematopoietic compartments and may lead to novel regenerative therapies.

Animals↗

PubMed2002

A molecular programme for the specification of germ cell fate in mice.

Germ cell fate in mice is induced in proximal epiblast cells by the extra-embryonic ectoderm, and is not acquired through the inheritance of any preformed germ plasm. To determine precisely how germ cells are specified, we performed a genetic screen between single nascent germ cells and their somatic neighbours that share common ancestry. Here we show that fragilis, an interferon-inducible transmembrane protein, marks the onset of germ cell competence, and we propose that through homotypic association, it demarcates germ cells from somatic neighbours. Using single-cell gene expression profiles, we also show that only those cells with the highest expression of fragilis subsequently express stella, a gene that we detected exclusively in lineage-restricted germ cells. The stella positive nascent germ cells exhibit repression of homeobox genes, which may explain their escape from a somatic cell fate and the retention of pluripotency.

Animals↗

PubMed2002

Ah, sweet mystery of death! Galectins and control of cell fate.

Control of cell death is critical in eukaryotic development, immune system homeostasis, and control of tumorigenesis. The galectin family of lectins is implicated in all of these processes. Other families of molecules function as death receptors or death effectors, but galectins are uniquely capable of acting both extracellularly and intracellularly to control cell death. Extracellularly, galectins cross-link glycan ligands to transduce signals that lead directly to death or that influence other signals regulating cell fate. Intracellular expression of galectins can modulate other signals controlling cell viability. Individual galectins can act on multiple cell types, and multiple galectins can act on the same cell. Understanding how galectins regulate cell viability and function will broaden our knowledge of the roles of galectins in basic biological processes and facilitate development of therapeutic applications for galectins in autoimmunity, transplant-related disease, and cancer.

Animals↗

PubMed1992

From cell fates to morphology: developmental genetics of the Caenorhabditis elegans male tail.

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.

Animals↗

PubMed1999

prx-1 functions cooperatively with another paired-related homeobox gene, prx-2, to maintain cell fates within the craniofacial mesenchyme.

The paired-related homeobox gene, prx-1, is expressed in the postmigratory cranial mesenchyme of all facial prominences and is required for the formation of proximal first arch derivatives. We introduced lacZ into the prx-1 locus to study the developmental fate of cells destined to express prx-1 in the prx-1 mutant background. lacZ was normally expressed in prx-1(neo); prx-1(lacZ )mutant craniofacial mesenchyme up until 11.5 d.p.c. At later time points, lacZ expression was lost from structures that are defective in the prx-1(neo) mutant mice. A related gene, prx-2, demonstrated overlapping expression with prx-1. To test the idea that prx-1 and prx-2 perform redundant functions, we generated prx-1(neo;)prx-2 compound mutant mice. Double mutant mice had novel phenotypes in which the rostral aspect of the mandible was defective, the mandibular incisor arrested as a single, bud-stage tooth germ and Meckel's cartilage was absent. Expression of two markers for tooth development, pax9 and patched, were downregulated. Using a transgene that marks a subset of prx-1-expressing cells in the craniofacial mesenchyme, we showed that cells within the hyoid arch take on the properties of the first branchial arch. These data suggest that prx-1 and prx-2 coordinately regulate gene expression in cells that contribute to the distal aspects of the mandibular arch mesenchyme and that prx-1 and prx-2 play a role in the maintenance of cell fate within the craniofacial mesenchyme.

Alleles↗

PubMed2000

Cell fate decisions in a human retinal precursor cell line: basic fibroblast growth factor- and transforming growth factor-alpha-mediated differentiation.

The purpose of this study was to determine if immortalized human retinal precursor cells could serve as a model to investigate cues that modulate cell fate and differentiation. We investigated the effects of a variety of growth factors broadly but specifically tested the effects of basic fibroblast growth factor (bFGF) and transforming growth factor (TGF)a in retinal cell differentiation and commitment. To determine the role of exogenously added growth factors in a human retinal precursor cell line (KGLDMSM), established from a first-trimester retina, cells were adapted to grow in a defined medium and exposed to a variety of trophic factors (epidermal growth factor [EGF], neuron growth factor [NGF], TGFalpha, TGFbeta, acidic FGF, and bFGF). Dose-response curves were developed to arrive at optimal concentrations. The neurotrophic potential of growth factors was determined by 3H-thymidine incorporation and bromodeoxyuridine (BrdU) labeling. The identity of the emerging neuronal phenotypes were determined by phase-contrast microscopy, immunolabeling for the neuron-specific antigens neurofilament protein (NF) and neuron-specific enolases (NSE), and photoreceptor-specific antigens (Rho1D4, 7G6) using immunocytochemistry and Western blot analysis. To identify some of the early response genes (c-fos, c-myc) expressed in response to growth factors, Northern blot analysis was performed. Almost all of the factors tested increased the total number of cells with a neuronal phenotype. Potency of growth factors to generate neurons was TGFalpha > bFGF > EGF > NGF. Both TGFalpha and bFGF, alone or in combination, increased the total number of neurons. Most of the neurons generated were photoreceptors, as depicted by the polarized phenotype, expression of photoreceptor-specific antigens, and processes resembling rudimentary outer segments. The increase in photoreceptor-like neurons is possibly attributable to an increase in numbers rather than greater survival. Additionally, the majority of the photoreceptors generated labeled with BrdU and for photoreceptor-specific antigens, suggesting that an inductive effect of bFGF and TGFalpha could occur in the cell cycle or shortly thereafter. Both bFGF and TGFalpha induced the expression of the early response gene c-fos while not altering the expression of c-actin or c-myc. The emergence of a photoreceptor phenotype was confirmed by both immunocytochemistry and Western blot analysis. The immortalized retinal precursor cell line could prove valuable in determining the role of exogenously added growth factors in retinal development and differentiation. Both bFGF and TGFalpha enhance the photoreceptor phenotype in medium-density cultures under conditions of defined medium. The same was confirmed by phase-contrast microscopy, immunocytochemistry, and Western blot analysis. Furthermore, cell fate determination in cultured precursor cells could occur during the late part of the cell cycle or shortly after completion of cell division. The effects of TGFalpha and bFGF seem to be slightly additive. The cell line will be extremely valuable in studying mechanisms of cell commitment and generation of retinal cell types, which could be tested for their potential for transplantation.

Cell Differentiation↗

PubMed2001

ENDOSPERM DEVELOPMENT: Cellularization and Cell Fate Specification.

The endosperm develops from the central cell of the megagametophyte after introduction of the second male gamete into the diploid central cell. Of the three forms of endosperm in angiosperms, the nuclear type is prevalent in economically important species, including the cereals. Landmarks in nuclear endosperm development are the coenocytic, cellularization, differentiation, and maturation stages. The differentiated endosperm contains four major cell types: starchy endosperm, aleurone, transfer cells, and the cells of the embryo surrounding region. Recent research has demonstrated that the first two phases of endosperm occur via mechanisms that are conserved among all groups of angiosperms, involving directed nuclear migration during the coenocytic stage and anticlinal cell wall deposition by cytoplasmic phragmoplasts formed in interzones between radial microtubular systems emanating from nuclear membranes. Complete cellularization of the endosperm coenocyte is achieved through centripetal growth of cell files, extending to the center of the endosperm cavity. Key points in cell cycle control and control of the MT (microtubular) cytoskeletal apparatus central to endosperm development are discussed. Specification of cell fates in the cereal endosperm appears to occur via positional signaling; cells in peripheral positions, except over the main vascular tissues, assume aleurone cell fate. Cells over the main vascular tissue become transfer cells and all interior cells become starchy endosperm cells. Studies in maize have implicated Crinkly4, a protein receptor kinase-like molecule, in aleurone cell fate specification.

Journal Article↗