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At least 163 records · Page 9Linked to original sources
PubMed2000

Overexpression of FGF-2 alters cell fate specification in the developing retina of Xenopus laevis.

The developing vertebrate retina produces appropriate ratios of seven phenotypically and functionally distinct cell types. Retinal progenitors remain multipotent up until the last cell division, favoring the idea that extrinsic cues direct cell fate. We demonstrated previously that fibroblast growth factor (FGF) receptors are necessary for transduction of signals in the developing Xenopus retina that bias cell fate decisions (S. McFarlane et al., 1998, Development 125, 3967-3975). However, the precise identity of the signal remains unknown. To test whether an FGF signal is sufficient to influence cell fate choices in the developing retina, FGF-2 was overexpressed in Xenopus retinal precursors by injecting, at the embryonic 16-cell stage, a cDNA plasmid encoding FGF-2 into cells fated to form the retina. We found that FGF-2 overexpression in retinal precursors altered the relative numbers of transgene-expressing retinal ganglion cells (RGC) and Müller glia; RGCs were increased by 35% and Müller glia decreased by 50%. In contrast, the proportion of retinal precursors that became photoreceptors was unchanged. Within the photoreceptor population, however, we found a twofold increase in rod photoreceptors at the expense of cone photoreceptors. These data are consistent with an endogenous FGF signal influencing cell fate decisions in the developing vertebrate retina.

Animals↗
PubMed2005

The CRAL/TRIO and GOLD domain protein CGR-1 promotes induction of vulval cell fates in Caenorhabditis elegans and interacts genetically with the Ras signaling pathway.

Ras-mediated signaling is necessary for the induction of vulval cell fates during Caenorhabditis elegans development. We identified cgr-1 by screening for suppressors of the ectopic vulval cell fates caused by a gain-of-function mutation of the let-60 ras gene. Analysis of two cgr-1 loss-of-function mutations indicates that cgr-1 positively regulates induction of vulval cell fates. cgr-1 is likely to function at a step in the Ras signaling pathway that is downstream of let-60, which encodes Ras, and upstream of lin-1, which encodes a transcription factor, if these genes function in a linear signaling pathway. These genetic studies are also consistent with the model that cgr-1 functions in a parallel pathway that promotes vulval cell fates. Localized expression studies suggest that cgr-1 functions cell autonomously to affect vulval cell fates. cgr-1 also functions early in development, since cgr-1 is necessary for larval viability. CGR-1 contains a CRAL/TRIO domain likely to bind a small hydrophobic ligand and a GOLD domain that may mediate interactions with proteins. A bioinformatic analysis revealed that there is a conserved family of CRAL/TRIO and GOLD domain-containing proteins that includes members from vertebrates and Drosophila. The analysis of cgr-1 identifies a novel in vivo function for a member of this family and a potential new regulator of Ras-mediated signaling.

Amino Acid Sequence↗
PubMed2026

Pri micropeptide functions as a cell-intrinsic timer controlling the transient phase of cell fate induction.

During development, cells sequentially acquire specific fates through temporally ordered regulatory systems. To ensure the harmonious progression, each system must be activated and subsequently inactivated at the appropriate time. In this study, we show that the duration of fate induction is controlled by the transient expression of polished rice (pri), a gene encoding micropeptides, during Drosophila tracheal development. pri is transiently expressed in prospective tracheal placodes and precedes the expression of trachealess (trh), a master transcription factor that initiates tracheal fate. pri induces the expression of trh through promoting the disappearance of the repressor form of the transcriptional factor Shavenbaby (Svb). Conversely, after placode invagination, artificially prolonging pri expression or constitutive loss of Svb leads to ectopic maintenance of trh expression in noninvaginated placode cells surrounding the properly invaginated domain. These results indicate that the rapid disappearance of pri properly terminates the initial fate induction system and suggest that this termination ensures a smooth transition to the subsequent fate-regulatory program-that is, the maintenance of tracheal cell fate specifically in the invaginated cells. Together, we propose that the transiency of pri serves as a cell-intrinsic molecular timer that controls the transient phase of cell fate induction and ensures the transition between sequential fate-regulatory systems, thereby enabling the precise coordination of cell identity with morphogenesis during organogenesis.

Animals↗
PubMed2006

Pax2 regulates neuronal-glial cell fate choice in the embryonic optic nerve.

During development, neural cell fate in the vertebrate optic nerve is restricted to the astroglial lineage. However, when isolated from the embryo and explanted in vitro, optic nerve progenitors generate neurons instead of astrocytes, suggesting that neuronal potentialities exist and are repressed in progenitors in vivo. Here we have investigated the mechanisms controlling cell fate in the optic nerve. The optic nerve is characterized by expression of the homeodomain transcription factor Pax2 which is maintained in differentiated astrocytes. We have observed that Pax2 is rapidly down-regulated in explanted optic nerves that generate neurons, and that its overexpression by electroporation in the optic nerve, or ectopically in the neural tube, is sufficient to block neuronal differentiation and allow glial development, showing that Pax2 plays a major role in controlling cell fate in the optic nerve. In vitro and ex vivo experiments further show that a signaling cascade that involves successively Sonic hedgehog and FGF is required to maintain Pax2 expression in optic nerve precursors whereby inhibiting the neuronal fate and promoting astroglial differentiation.

Animals↗
PubMed1990

The Caenorhabditis elegans gene lin-10 is broadly expressed while required specifically for the determination of vulval cell fates.

As a first step in a molecular dissection of the pathway controlling the determination of vulval cell fates in Caenorhabditis elegans, we have analyzed the gene lin-10. We show that loss-of-function mutations in this gene specifically prevent the induction of vulval cell lineages and result instead in the expression of hypodermal cell lineages. We isolated a transposon-insertion allele of lin-10 and used it to clone a genomic region that contains the lin-10 locus. The location of lin-10 within this region was determined by identifying a transcript affected by three independent lin-10 mutations and by delimiting the minimal segment of DNA sufficient to rescue the lin-10 mutant phenotype in germ line transformation experiments. The predicted lin-10 protein sequence is not similar to sequences in current data bases, suggesting that lin-10 defines a novel class of gene involved in the specification of cell fates. Although our genetic studies indicate that lin-10 is required specifically for the determination of vulval cell fates, lin-10 transcripts are present in cells other than vulval precursor cells. This result suggests that lin-10 may have a general but redundant role in development, functioning in diverse cell lineages to control cell fates. Alternatively, lin-10 may function specifically in vulval development, in which case lin-10 activity could be regulated at a post-transcriptional level or could have biological consequences only in conjunction with the products of other genes.

Alleles↗
PubMed1994

The TRH neuronal phenotype forms embryonic cell clusters that go on to establish a regionalized cell fate in forebrain.

How neurons diversify in developing brain to produce discrete cell fates in their appropriate regions remains a fundamental question. Embryonic Xenopus was previously used to identify juxtaposed embryonic cells that first express proopiomelanocortin mRNA in forebrain and pituitary, supporting the idea that this neuropeptide phenotype is induced locally (Hayes and Loh, 1990, Development 110: 747-757). To begin to examine how a more widespread population of forebrain cells is set up, the present focus is on the thyrotropin-releasing hormone (TRH) phenotype. Serial section in situ hybridization histochemistry produced the unexpected finding that the adult-like TRH system spanning forebrain and comprising over six different telencephalic and diencephalic nuclei, is preceded by an embryonic TRH cell population that is initially localized and then highly regionalized in the area from which the adult pattern develops. Thus, the first TRH cells, detected in vivo after 35h (stage 29/30), were confined to discrete anterior or posterior bilateral clusters in embryonic forebrain or hindbrain. Thereafter, the TRH cell clusters in diencephalon, but not hindbrain, expanded to form rows, extending anteriorly into telencephalon and bifurcating posteriorly around the infundibulum. By 80 h (stage 42), after extensive brain morphogenesis, these forebrain rows showed regional differences in levels of TRH mRNA corresponding to the specific brain nuclei that have been shown to contain TRH cells in adult. These findings show that subsets of phenotype-specific forebrain cells first form a regionalized neuronal cell fate before distinct brain nuclei form. This in turn points to the testable hypothesis in Xenopus that certain neuronal cell fates in forebrain may be dictated by cell lineage or local induction.

Animals↗
PubMed2005

Functional avidity directs T-cell fate in autoreactive CD4+ T cells.

Major histocompatibility complex class II tetramer staining and activation analysis identified 2 distinct types of antigen-specific CD4+ T cells in the peripheral blood of humans with type 1 (autoimmune) diabetes. T cells with low-avidity recognition of peptide-MHC ligands had low sensitivity to activation and inefficient activation-induced apoptosis. In contrast, high-avidity T cells were highly sensitive to antigen-induced cell death through apoptotic mechanisms, and both apoptosis-resistant high- and low-avidity T cells that survived prolonged tetramer treatment were rendered anergic to restimulation by antigen. In addition, however, apoptosis-resistant high-avidity T cells acquired regulatory features, being able to suppress both antigen-specific and nonspecific CD4+ T-cell responses. This suppression was contact-dependent and correlated with the down-regulation of HLA class II and costimulatory molecules on antigen-presenting cells, including B cells and dendritic cells. T cells face a variety of fates following antigen exposure, including the paradoxic maintenance of high-avidity autoreactive T cells in the peripheral circulation, perhaps due to this capability of acquiring anergic and suppressive properties. Regulation via down-modulation of antigen-presenting cell function, a form of cell-to-cell licensing for suppression, also offers possibilities for the application of peptide-MHC therapeutics.

Adolescent↗
PubMed2026

Metabolic atlas of early human cortex reveals glycolytic remodeling and pentose phosphate pathway control of cell fate transitions.

Cortical development involves rapid progenitor expansion and cell diversification supported by tightly regulated metabolic programs, yet these programs remain largely uncharacterized in human development. Here, we generated a metabolic atlas of the early human cortex using primary tissue and stem cell-derived cortical organoids. We observed dynamic changes in core metabolic functions, including an unexpected increase in glycolysis and pentose phosphate pathway (PPP) activity during late neurogenesis. Manipulation of glucose availability in cortical organoids altered cell-type composition, increasing outer radial glia (oRG) and inhibitory neuron populations. Pharmacological and genetic inhibition of PPP enzymes recapitulated these cell fate changes. Ribose was sufficient to rescue radial glia (RG) gene expression changes, revert organoid cell-type composition, and restore levels of ATP and hypotaurine. These data identify a critical role for the PPP in modulating RG cell fate specification and generate a resource for future exploration of additional metabolic pathways in human cortical development.

cell fate↗
PubMed2002

CD123bright plasmacytoid predendritic cells: progenitors undergoing cell fate conversion?

CD123(bright) plasmacytoid cells (PC) and CD1c(+) peripheral blood myeloid dendritic cells (DC) are two human DC precursors that can be expanded in vivo by Fms-like tyrosine kinase 3 ligand (FL). It has been proposed that PC and myeloid CD1c(+) DC may represent two distinct lineages of DC. However, the phylogenetic affiliation of PC and its relationship with myeloid DC remain controversial. Here we show that CD123(bright)HLA-DR(+) PC from FL-treated healthy volunteers can be divided into mutually exclusive subsets that harbor either lymphoid or myeloid features. Lymphoid-like PC represent the majority of PC and include pTalpha-, CD3epsilon-, and CD7-expressing cells. They exhibit TCR-beta gene loci in germline configuration and show low allostimulatory capacity, but produce type I IFN upon virus infection and can be differentiated in vitro into potent APC. Myeloid-like PC represent a minor fraction of the total PC population. They exhibit a striking PC/myeloid DC intermediate phenotype (CD5(+)CD11c(low)CD45RA(low)CD45RO(-)CD101(+)), produce proinflammatory cytokines, and do not require in vitro maturation to act as potent APCs. We propose that, rather than forming a lineage, PC might represent a population of lymphoid cells undergoing an in vivo cell fate conversion from a lymphoid to a myeloid cell type.

Antigen-Presenting Cells↗
PubMed2026

Mapping self-associating chromatin hubs identifies Id proteins as key determinants of exhausted CD8+ T cell fate.

Within days of exposure to chronic viral infections, activated CD8+ T cells differentiate into Tcf1-Slamf6loTim3hi exhaustion-prone effector T (TEX_EFF) cells or self-renewing Tcf1+Slamf6hiTim3lo precursor exhausted T (TPEX) cells. Here we showed that early CD8+ TEX cell fates were imprinted by forming subset-specific, self-associating chromatin hubs. Chromatin hub assembly coincided with effector or stemness gene induction and identified the transcription cofactors Id2 and Id3 as key regulators that promoted CD8+ TEX_EFF and CD8+ TPEX cell fates, respectively. Id2 drove CD8+ TEX_EFF cell specification by activating effector genes, while suppressing genes involved in exhaustion and stemness. In contrast, Id3-repressed effector genes but upregulated IL-7Rα and AhR, thereby maintaining the CD8+ TPEX cell pool. Mechanistically, Id2 and Id3 exhibited a distinct impact on the chromatin accessibility landscape in early CD8+ TEX cells by engaging Runx3 and Tcf1 transcription factors along with E proteins. These findings indicated that reshaping chromatin architecture represents a critical means for specifying CD8+ TEX cell fates and ensuring lineage stability.

Animals↗
PubMed2002

Musashi: a translational regulator of cell fate.

Transcription is thought to have a major role in the regulation of cell fate; the importance of translational regulation in this process has been less certain. Recent findings demonstrate that translational regulation contributes to cell-fate specification. The evolutionarily conserved, neural RNA-binding protein Musashi, for example, controls neural cell fate. The protein functions in maintenance of the stem-cell state, differentiation, and tumorigenesis by repressing translation of particular mRNAs. In mammals it might play an important role in activating Notch signalling by repressing translation of the Notch inhibitor m-Numb.

Animals↗
PubMed2006

Regulation of stem cell fate in hematopoietic development.

Stem cells are broadly classified into two categories; embryonic stem cell and somatic stem cell. Both types of stem cells can be differentiated into many cell types of the body with a different capability. Blood cells are examples of the cells that can be derived from both embryonic and somatic stem cells, both in vivo and in vitro. In adults, blood cells are mainly derived from hematopoietic stem cells (HSC) in the bone marrow. HSC growth and differentiation is tightly regulated which require both intrinsic and extrinsic signals. In this regard, transcription factors are critical for the development of HSC and specific cell lineages, in part, by regulating the expression of hematopoietic growth factor (HGF) receptors, other transcription factors and lineage specific genes transcription. This review will focus on the role of Id transcription factors in stem cell fate regulation.

Adult Stem Cells↗
PubMed2006

A default mechanism of spindle orientation based on cell shape is sufficient to generate cell fate diversity in polarised Xenopus blastomeres.

The process of oriented divisions of polarised cells is a recurrent mechanism of cell fate diversification in development. It is commonly assumed that a specialised mechanism of spindle alignment into the axis of polarity is a prerequisite for such systems to generate cell fate diversity. Oriented divisions also take place in the frog blastula, where orientation of the spindle into the apicobasal axis of polarised blastomeres generates inner and outer cells with different fates. Here, we show that, in this system, the spindle orients according to the shape of the cells, a mechanism often thought to be a default. We show that in the embryo, fatedifferentiative, perpendicular divisions correlate with a perpendicular long axis and a small apical surface, but the long axis rather then the size of the apical domain defines the division orientation. Mitotic spindles in rounded, yet polarised, isolated Xenopus blastula cells orient randomly, but align into an experimentally introduced long axis when cells are deformed early in the cell cycle. Unlike other systems of oriented divisions, the spindle aligns at prophase, rotation behaviour is rare and restricted to small angle adjustments. Disruption of astral microtubules leads to misalignment of the spindle. These results show that a mechanism of spindle orientation that depends on cell shape rather than cortical polarity can nevertheless generate cell fate diversity from a population of polarised cells.

Animals↗
PubMed2004

MTA3 and the Mi-2/NuRD complex regulate cell fate during B lymphocyte differentiation.

The transcriptional repressor BCL-6 regulates B lymphocyte cell fate during the germinal center reaction by preventing terminal differentiation of B lymphocytes into plasma cells until appropriate signals are received. Here, we report a cofactor, MTA3, a cell type-specific subunit of the corepressor complex Mi-2/NuRD, for BCL-6-dependent cell fate determination. MTA3 is expressed in the same pattern in germinal centers as BCL-6. BCL-6 physically interacts with Mi-2/NuRD and this interaction is sensitive to BCL-6 acetylation status. Depletion of MTA3 by RNAi impairs BCL-6-dependent repression and alters the cell-specific transcriptional pattern characteristic of the B lymphocyte. Remarkably, exogenous expression of BCL-6 in a plasma cell line leads, in an MTA3-dependent manner, to repression of plasma cell-specific transcripts, reactivation of the B cell transcriptional program, expression of B lymphocyte cell surface markers, and reprogramming of cell fate.

Acetylation↗
PubMed2000

Serrate and Notch specify cell fates in the heart field by suppressing cardiomyogenesis.

Notch signaling mediates numerous developmental cell fate decisions in organisms ranging from flies to humans, resulting in the generation of multiple cell types from equipotential precursors. In this paper, we present evidence that activation of Notch by its ligand Serrate apportions myogenic and non-myogenic cell fates within the early Xenopus heart field. The crescent-shaped field of heart mesoderm is specified initially as cardiomyogenic. While the ventral region of the field forms the myocardial tube, the dorsolateral portions lose myogenic potency and form the dorsal mesocardium and pericardial roof (Raffin, M., Leong, L. M., Rones, M. S., Sparrow, D., Mohun, T. and Mercola, M. (2000) Dev. Biol., 218, 326-340). The local interactions that establish or maintain the distinct myocardial and non-myocardial domains have never been described. Here we show that Xenopus Notch1 (Xotch) and Serrate1 are expressed in overlapping patterns in the early heart field. Conditional activation or inhibition of the Notch pathway with inducible dominant negative or active forms of the RBP-J/Suppressor of Hairless [Su(H)] transcription factor indicated that activation of Notch feeds back on Serrate1 gene expression to localize transcripts more dorsolaterally than those of Notch1, with overlap in the region of the developing mesocardium. Moreover, Notch pathway activation decreased myocardial gene expression and increased expression of a marker of the mesocardium and pericardial roof, whereas inhibition of Notch signaling had the opposite effect. Activation or inhibition of Notch also regulated contribution of individual cells to the myocardium. Importantly, expression of Nkx2. 5 and Gata4 remained largely unaffected, indicating that Notch signaling functions downstream of heart field specification. We conclude that Notch signaling through Su(H) suppresses cardiomyogenesis and that this activity is essential for the correct specification of myocardial and non-myocardial cell fates.

Animals↗
PubMed2005

The HMX homeodomain protein MLS-2 regulates cleavage orientation, cell proliferation and cell fate specification in the C. elegans postembryonic mesoderm.

The proper formation of a complex multicellular organism requires the precise coordination of many cellular events, including cell proliferation, cell fate specification and differentiation. The C. elegans postembryonic mesodermal lineage, the M lineage, allows us to study mechanisms coordinating these events at single cell resolution. We have identified an HMX homeodomain protein MLS-2 in a screen for factors required for M lineage patterning. The MLS-2 protein is present in nuclei of undifferentiated cells in the early M lineage and in a subset of head neurons. In the M lineage, MLS-2 activity appears to be tightly regulated at the fourth round of cell division, coincident with the transition from proliferation to differentiation. A predicted null allele of mls-2, cc615, causes reduced cell proliferation in the M lineage, whereas a semi-dominant, gain-of-function allele, tm252, results in increased cell proliferation. Loss or overexpression of mls-2 also affects cleavage orientation and cell fate specification in the M lineage. We show that the increased cell proliferation in mls-2(tm252) mutants requires CYE-1, a G1 cell cycle regulator. Furthermore, the C. elegans Myod homolog HLH-1 acts downstream of mls-2 to specify M-derived coelomocyte cell fates. Thus MLS-2 functions in a cell type-specific manner to regulate both cell proliferation and cell fate specification.

Amino Acid Sequence↗
PubMed2006

In vivo MRI of cancer cell fate at the single-cell level in a mouse model of breast cancer metastasis to the brain.

Metastasis (the spread of cancer from a primary tumor to secondary organs) is responsible for most cancer deaths. The ability to follow the fate of a population of tumor cells over time in an experimental animal would provide a powerful new way to monitor the metastatic process. Here we describe a magnetic resonance imaging (MRI) technique that permits the tracking of breast cancer cells in a mouse model of brain metastasis at the single-cell level. Cancer cells that were injected into the left ventricle of the mouse heart and then delivered to the brain were detectable on MR images. This allowed the visualization of the initial delivery and distribution of cells, as well as the growth of tumors from a subset of these cells within the whole intact brain volume. The ability to follow the metastatic process from the single-cell stage through metastatic growth, and to quantify and monitor the presence of solitary undivided cells will facilitate progress in understanding the mechanisms of brain metastasis and tumor dormancy, and the development of therapeutics to treat this disease.

Animals↗
PubMed1996

Gene targeting reveals a hierarchy of transcription factors regulating specification of lymphoid cell fates.

Specification of B- and T-lymphoid cell fates appears to involve the expression of a shared set of genes encoding recombination proteins and of genes encoding lineage-specific components of antigen receptors. Recent studies using gene targeting have identified transcription factors that are required for the proper specification of lymphoid cell fates. On the basis of these data, a regulatory gene hierarchy which orchestrates the development of lymphoid progenitors from hematopoietic stem cells can be proposed.

Animals↗