Intrinsic Transcription Factors Research Articles

The transcription factor Pou3f1 promotes neural fate commitment via activation of neural lineage genes and inhibition of external signaling pathways.

The neural fate commitment of pluripotent stem cells requires the repression of extrinsic inhibitory signals and the activation of intrinsic positive transcription factors. However, how these two events are integrated to ensure appropriate neural conversion remains unclear. In this study, we showed that Pou3f1 is essential for the neural differentiation of mouse embryonic stem cells (ESCs), specifically during the transition from epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs). Chimeric analysis showed that Pou3f1 knockdown leads to a markedly decreased incorporation of ESCs in the neuroectoderm. By contrast, Pou3f1-overexpressing ESC derivatives preferentially contribute to the neuroectoderm. Genome-wide ChIP-seq and RNA-seq analyses indicated that Pou3f1 is an upstream activator of neural lineage genes, and also is a repressor of BMP and Wnt signaling. Our results established that Pou3f1 promotes the neural fate commitment of pluripotent stem cells through a dual role, activating internal neural induction programs and antagonizing extrinsic neural inhibitory signals.

The ventricular-subventricular zone: a source of oligodendrocytes in the adult brain.

The ventricular-subventricular zone: a source of oligodendrocytes in the adult brain.

A liaison between intrinsic and extrinsic regulators of pluripotency

A pluripotent cell state is regulated by complex transcription factor network under the control of extrinsic signals, so that undifferentiated cells can readily commit to any cell lineages in response to appropriate stimuli. A number of recent studies using pluripotent stem cells in vitro have shown that maintenance of pluripotency can be achieved with different combinations of extrinsic factors, yet by activating common intrinsic regulators. Two papers in this issue of The EMBO Journal identified Tfcp2l1 (also known as Crtr‐1 or Tcfcp2l1) as a factor on which activating and repressing stimuli for pluripotency converge. The results provide insight into how intrinsic pluripotency regulatory network is stably organized downstream of diverse inputs. Pluripotent stem cells in early embryos are transient cell populations that exist in the epiblast of the peri‐implantation embryos, but can be captured in vitro as embryonic stem cells (ESCs). ESCs self‐renew indefinitely while keeping the ability to differentiate into any cell lineages. Maintenance of self‐renewal in ESCs depends on self‐organizing transcriptional regulatory network, in which continuous inputs from extrinsic cues are required to sustain an intrinsic transcription factor (TF) circuitry. The most critical extrinsic regulators are leukaemia inhibitory factor (LIF) and its downstream effector Stat3. Although loss of zygotic Stat3 does not affect the embryonic development before gastrulation, a recent analysis of embryos lacking both maternal and zygotic Stat3 clearly revealed its indispensable role in the specification of the epiblast lineage around implantation (Do et al , 2013). However, consistent with other studies showing that lineage identities in early embryos …

Polycomb Determines Responses to Smad2/3 Signaling in Embryonic Stem Cell Differentiation and in Reprogramming

Integration of extrinsic signals, epigenetic regulators, and intrinsic transcription factors establishes pluripotent stem cell identity. Interplay between these components also underlies the capacity of stem cells to undergo differentiation, and of differentiated cells to re-establish the pluripotent state in direct reprogramming. Polycomb repressive complexes are epigenetic regulators that play key roles in stem cell identity and in differentiated cell fates. Smad2 and Smad3 (Smad2/3), the intracellular mediators of the Nodal/Activin/transforming growth factor (TGF) β cell-cell signaling pathway also are implicated in stem cell pluripotency and in differentiation. Here, we show that Polycomb imposes responses to Smad2/3-mediated signaling to selectively regulate expression of the master pluripotency factor Oct 4 during initiation of differentiation, but not in the self-renewing pluripotent ground state. During reprogramming back to the ground state, we find that the enhancement of reprogramming efficiency stemming from blocking Nodal/Activin/TGFβ signaling also depends on Polycomb. These context-dependent responses to Smad2/3 imposed by Polycomb action provide a mechanism for selective gene regulation that can reconcile the apparently conflicting roles of this signaling pathway in pluripotency, differentiation, and reprogramming.

T Cell Transcription Factors and Their Impact on HIV Expression

By targeting CD4+ effector T cells, HIV has a dramatic impact on the depletion, expansion and function of the different polarized T cell subsets. The maturation of T cell lineages is in part driven by intrinsic transcription factors that potentially influence how efficiently HIV replicates. In this review, we explore whether transcription factors that are required for polarizing T cells influence HIV replication. In particular, we examine provirus transcription as well as the establishment and maintenance of HIV latency. Furthermore, it is suggested these factors may provide novel cell-specific therapeutic strategies for targeting the HIV latent reservoir.

Retinal differentiation in Drosophila

Drosophila eye development has been extensively studied, due to the ease of genetic screens for mutations disrupting this process. The eye imaginal disc is specified during embryonic and larval development by the Pax6 homolog Eyeless and a network of downstream transcription factors. Expression of these factors is regulated by signaling molecules and also indirectly by growth of the eye disc. Differentiation of photoreceptor clusters initiates in the third larval instar at the posterior of the eye disc and progresses anteriorly, driven by the secreted protein Hedgehog. Within each cluster, the combined activities of Hedgehog signaling and Notch-mediated lateral inhibition induce and refine the expression of the transcription factor Atonal, which specifies the founding R8 photoreceptor of each ommatidium. Seven additional photoreceptors, followed by cone and pigment cells, are successively recruited by the signaling molecules Spitz, Delta, and Bride of sevenless. Combinations of these signals and of intrinsic transcription factors give each ommatidial cell its specific identity. During the pupal stages, rhodopsins are expressed, and the photoreceptors and accessory cells take on their final positions and morphologies to form the adult retina. Over the past few decades, the genetic analysis of this small number of cell types arranged in a repetitive structure has allowed a remarkably detailed understanding of the basic mechanisms controlling cell differentiation and morphological rearrangement.

Centrosome movements in vivo correlate with specific neurite formation downstream of LIM homeodomain transcription factor activity

Neurons must develop complex structure to form proper connections in the nervous system. The initiation of axons in defined locations on the cell body and their extension to synaptic targets are critical steps in neuronal morphogenesis, yet the mechanisms controlling axon formation in vivo are poorly understood. The centrosome has been implicated in multiple aspects of neuronal morphogenesis; however, its function in axon development is under debate. Conflicting results from studies of centrosome function in axonogenesis suggest that its role is context dependent and underscore the importance of studying centrosome function as neurons develop in their natural environment. Using live imaging of zebrafish Rohon-Beard (RB) sensory neurons in vivo, we discovered a spatiotemporal relationship between centrosome position and the formation of RB peripheral, but not central, axons. We tested centrosome function by laser ablation and found that centrosome disruption inhibited peripheral axon outgrowth. In addition, we show that centrosome position and motility are regulated by LIM homeodomain transcription factor activity, which is specifically required for the development of RB peripheral axons. Furthermore, we show a correlation between centrosome mislocalization and ectopic axon formation in bashful (laminin alpha 1) mutants. Thus, both intrinsic transcription factor activity and extracellular cues can influence centrosome position and axon formation in vivo. This study presents the first positive association between the centrosome and axon formation in vivo and suggests that the centrosome is important for differential neurite formation in neurons with complex axonal morphologies.

Centrosome movements in vivo correlate with specific neurite formation downstream of LIM homeodomain transcription factor activity

Neurons must develop complex structure to form proper connections in the nervous system. The initiation of axons in defined locations on the cell body and their extension to synaptic targets are critical steps in neuronal morphogenesis, yet the mechanisms controlling axon formation in vivo are poorly understood. The centrosome has been implicated in multiple aspects of neuronal morphogenesis; however, its function in axon development is under debate. Conflicting results from studies of centrosome function in axonogenesis suggest that its role is context dependent and underscore the importance of studying centrosome function as neurons develop in their natural environment. Using live imaging of zebrafish Rohon-Beard (RB) sensory neurons in vivo, we discovered a spatiotemporal relationship between centrosome position and the formation of RB peripheral, but not central, axons. We tested centrosome function by laser ablation and found that centrosome disruption inhibited peripheral axon outgrowth. In addition, we show that centrosome position and motility are regulated by LIM homeodomain transcription factor activity, which is specifically required for the development of RB peripheral axons. Furthermore, we show a correlation between centrosome mislocalization and ectopic axon formation in bashful (laminin alpha 1) mutants. Thus, both intrinsic transcription factor activity and extracellular cues can influence centrosome position and axon formation in vivo. This study presents the first positive association between the centrosome and axon formation in vivo and suggests that the centrosome is important for differential neurite formation in neurons with complex axonal morphologies.

A STATus report on DC development

DCs have a vital role in the immune system by recognizing exogenous or self-antigens and eliciting appropriate stimulatory or tolerogenic adaptive immune responses. DCs also contribute to human autoimmune disease and, when depleted, to immunodeficiency. Moreover, DCs are being explored for potential use in clinical therapies including cancer treatment. Thus, understanding the molecular mechanisms that regulate DCs is crucial to improving treatments for human immune disease and cancer. DCs constitute a heterogeneous population including plasmacytoid (pDC) and classic (cDC) subsets; however, the majority of DCs residing in lymphoid organs and peripheral tissues in steady state share common progenitor populations, originating with hematopoietic stem cells. Like other hematopoietic lineages, DCs require extracellular factors including cytokines, as well as intrinsic transcription factors, to control lineage specification, commitment, and maturation. Here, we review recent findings on the roles for cytokines and cytokine-activated STAT transcription factors in DC subset development. We also discuss how cytokines and STATs intersect with lineage-regulatory transcription factors and how insight into the molecular basis of human disease has revealed transcriptional regulators of DCs. Whereas this is an emerging area with much work remaining, we anticipate that knowledge gained by delineating cytokine and transcription factor mechanisms will enable a better understanding of DC subset diversity, and the potential to manipulate these important immune cells for human benefit.

Epigenetic regulation of retinal development and disease

Epigenetic regulation, including DNA methylation, histone modifications, and chromosomal organization, is emerging as a new layer of transcriptional regulation in retinal development and maintenance. Guided by intrinsic transcription factors and extrinsic signaling molecules, epigenetic regulation can activate and/or repress the expression of specific sets of genes, therefore playing an important role in retinal cell fate specification and terminal differentiation during development as well as maintaining cell function and survival in adults. Here, we review the major findings that have linked these mechanisms to the development and maintenance of retinal structure and function, with a focus on ganglion cells and photoreceptors. The mechanisms of epigenetic regulation are highly complex and vary among different cell types. Understanding the basic principles of these mechanisms and their regulatory pathways may provide new insight into the pathogenesis of retinal diseases associated with transcription dysregulation, and new therapeutic strategies for treatment.

In vivo imaging of cell behaviors and F-actin reveals LIM-HD transcription factor regulation of peripheral versus central sensory axon development

BackgroundDevelopment of specific neuronal morphology requires precise control over cell motility processes, including axon formation, outgrowth and branching. Dynamic remodeling of the filamentous actin (F-actin) cytoskeleton is critical for these processes; however, little is known about the mechanisms controlling motile axon behaviors and F-actin dynamics in vivo. Neuronal structure is specified in part by intrinsic transcription factor activity, yet the molecular and cellular steps between transcription and axon behavior are not well understood. Zebrafish Rohon-Beard (RB) sensory neurons have a unique morphology, with central axons that extend in the spinal cord and a peripheral axon that innervates the skin. LIM homeodomain (LIM-HD) transcription factor activity is required for formation of peripheral RB axons. To understand how neuronal morphogenesis is controlled in vivo and how LIM-HD transcription factor activity differentially regulates peripheral versus central axons, we used live imaging of axon behavior and F-actin distribution in vivo.ResultsWe used an F-actin biosensor containing the actin-binding domain of utrophin to characterize actin rearrangements during specific developmental processes in vivo, including axon initiation, consolidation and branching. We found that peripheral axons initiate from a specific cellular compartment and that F-actin accumulation and protrusive activity precede peripheral axon initiation. Moreover, disruption of LIM-HD transcriptional activity has different effects on the motility of peripheral versus central axons; it inhibits peripheral axon initiation, growth and branching, while increasing the growth rate of central axons. Our imaging revealed that LIM-HD transcription factor activity is not required for F-actin based protrusive activity or F-actin accumulation during peripheral axon initiation, but can affect positioning of F-actin accumulation and axon formation.ConclusionOur ability to image the dynamics of F-actin distribution during neuronal morphogenesis in vivo is unprecedented, and our experiments provide insight into the regulation of cell motility as neurons develop in the intact embryo. We identify specific motile cell behaviors affected by LIM-HD transcription factor activity and reveal how transcription factors differentially control the formation and growth of two axons from the same neuron.

Essential role of the N-terminal region of TFII-I in viability and behavior

BackgroundGTF2I codes for a general intrinsic transcription factor and calcium channel regulator TFII-I, with high and ubiquitous expression, and a strong candidate for involvement in the morphological and neuro-developmental anomalies of the Williams-Beuren syndrome (WBS). WBS is a genetic disorder due to a recurring deletion of about 1,55-1,83 Mb containing 25-28 genes in chromosome band 7q11.23 including GTF2I. Completed homozygous loss of either the Gtf2i or Gtf2ird1 function in mice provided additional evidence for the involvement of both genes in the craniofacial and cognitive phenotype. Unfortunately nothing is now about the behavioral characterization of heterozygous mice.MethodsBy gene targeting we have generated a mutant mice with a deletion of the first 140 amino-acids of TFII-I. mRNA and protein expression analysis were used to document the effect of the study deletion. We performed behavioral characterization of heterozygous mutant mice to document in vivo implications of TFII-I in the cognitive profile of WBS patients.ResultsHomozygous and heterozygous mutant mice exhibit craniofacial alterations, most clearly represented in homozygous condition. Behavioral test demonstrate that heterozygous mutant mice exhibit some neurobehavioral alterations and hyperacusis or odynacusis that could be associated with specific features of WBS phenotype. Homozygous mutant mice present highly compromised embryonic viability and fertility. Regarding cellular model, we documented a retarded growth in heterozygous MEFs respect to homozygous or wild-type MEFs.ConclusionOur data confirm that, although additive effects of haploinsufficiency at several genes may contribute to the full craniofacial or neurocognitive features of WBS, correct expression of GTF2I is one of the main players. In addition, these findings show that the deletion of the fist 140 amino-acids of TFII-I altered it correct function leading to a clear phenotype, at both levels, at the cellular model and at the in vivo model.

Retinoid Signaling and Neurogenin2 Function Are Coupled for the Specification of Spinal Motor Neurons through a Chromatin Modifier CBP

Extracellular signals and cell-intrinsic transcription factors cooperatively instruct generation of diverse neurons. However, little is known about how neural progenitors integrate both cues and orchestrate chromatin changes for neuronal specification. Here, we report that extrinsic signal retinoic acid (RA) and intrinsic transcription factor Neurogenin2 (Ngn2) collaboratively trigger transcriptionally active chromatin in spinal motor neuron genes during development. Retinoic acid receptor (RAR) binds Ngn2 and is thereby recruited to motor neuron genes targeted by Ngn2. RA then facilitates the recruitment of a histone acetyltransferase CBP to the Ngn2/RAR-complex, markedly inducing histone H3/H4-acetylation. Correspondingly, timely inactivation of CBP and its paralog p300 results in profound defects in motor neuron specification and motor axonal projection, accompanied by significantly reduced histone H3-acetylation of the motor neuron enhancer. Our study uncovers the mechanism by which extrinsic RA-signal and intrinsic transcription factor Ngn2 cooperate for cell fate specification through their synergistic activity to trigger transcriptionally active chromatin.

Control of luminal type A intrinsic subtype enriched transcription factor network by insulin: implications of diabetes on breast cancer classification.

Abstract Abstract #3029 Background: Luminal type A and type B represent estrogen receptor alpha (ERalpha)-positive breast cancers with luminal type A expressing higher levels of ERalpha and is associated with better prognosis. Recent studies have identified a specific functional transcription factor network comprising GATA-3, FOXA1 and ERalpha in normal luminal cells as well as in luminal type A breast cancer that dictates their hormone dependence. Signaling molecules that may disrupt this network and force these cells to acquire hormone-independence are not known. T-bet (Tbx21) has been described as a major negative regulator of GATA-3 activity. As the expression and/or activity of some of the above factors are controlled by insulin, the objective of this study was to investigate whether elevated level of insulin, as evidenced in type II diabetes, alters gene expression pattern in luminal type A breast cancers by interrupting GATA-3:FOXA1:ERalpha network and thus forcing these cancers to acquire non-luminal phenotype and/or hormone-independence.
 Methodologies: The effect of insulin on the expression of ERalpha, FOXA1, GATA-3 and T-bet was measured in ERalpha-positive MCF-7 cells by Western blot analysis. The effect of T-bet on estrogen-regulated gene expression was measured by stable overexpression of T-bet in MCF-7 cells and subsequent qRT-PCR analysis. Publicly available Oncomine database was used to determine the expression pattern of T-bet and its relation to ERalpha status in primary breast cancers. A proliferation assay was used to determine sensitivity of T-bet overexpressing cells to tamoxifen in the presence and absence of insulin.
 Results: Insulin induced the expression of T-bet, which was partially reversed by estrogen. ERalpha and GATA-3 levels were reduced in MCF-7 cells stably overexpressing T-bet suggesting that T-bet reduces GATA-3-dependent ERalpha expression. Estrogen-inducible expression of estrogen target genes GREB-1 and Myb was lower in T-bet overexpressing cells compared to parental cells, although basal expression was elevated in T-bet overexpressing cells. Treatment of T-bet overexpressing cells with insulin decreased tamoxifen sensitivity. Although T-bet expression was generally higher in ERalpha-negative breast cancers compared to ERalpha-positive breast cancers, a subpopulation of ER-positive breast cancers express elevated levels of T-bet.
 Conclusions: Insulin may change the gene expression pattern through T-bet-mediated disruption of master cell-type-specific transcriptional network including GATA-3, ERalpha and FOXA1 that dictates the phenotype of hormone-dependent luminal type A breast cancer. T-bet may serve as a marker to identify ERalpha-positive breast cancers that express low levels of GATA-3 and have progressed to hormone-independence. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3029.

Sox9 Inhibits Wnt Signaling by Promoting β-Catenin Phosphorylation in the Nucleus

Chondrocyte fate determination and maintenance requires Sox9, an intrinsic transcription factor, but is inhibited by Wnt/beta-catenin signaling activated by extrinsic Wnt ligands. Here we explored the underlying molecular mechanism by which Sox9 antagonizes the Wnt/beta-catenin signaling in chondrocyte differentiation. We found that Sox9 employed two distinct mechanisms to inhibit Wnt/beta-catenin signaling: the Sox9 N terminus is necessary and sufficient to promote beta-catenin degradation, whereas the C terminus is required to inhibit beta-catenin transcriptional activity without affecting its stability. Sox9 binds to beta-catenin and components of the beta-catenin "destruction complex," glycogen synthase kinase 3 and beta-transducin repeat containing protein, to promote their nuclear localization. Independent of its DNA binding ability, nuclear localization of Sox9 is both necessary and sufficient to enhance beta-catenin phosphorylation and its subsequent degradation. Thus, one mechanism whereby Sox9 regulates chondrogenesis is to promote efficient beta-catenin phosphorylation in the nucleus. This mechanism may be broadly employed by other intrinsic cell fate determining transcription factors to promptly turn off extrinsic inhibitory Wnt signaling mediated by beta-catenin.

Pattern formation in the Drosophila eye disc

Differentiation of the Drosophila compound eye from the eye imaginal disc is a progressive process: columns of cells successively differentiate in a posterior to anterior sequence, clusters of cells form at regularly spaced intervals within each column, and individual photoreceptors differentiate in a defined order within each cluster. The progression of differentiation across the eye disc is driven by a positive autoregulatory loop of expression of the secreted molecule Hedgehog, which is temporally delayed by the intercalation of a second signal, Spitz. Hedgehog refines the spatial position at which each column initiates its differentiation by inducing secondary signals that act over different ranges to control the expression of positive and negative regulators. The position of clusters within each column is controlled by secreted inhibitory signals from clusters in the preceding column, and a single founder neuron, R8, is singled out within each cluster by Notch-mediated lateral inhibition. R8 then sequentially recruits surrounding cells to differentiate by producing a short-range signal, Spitz, which induces a secondary short-range signal, Delta. Intrinsic transcription factors act in combination with these two signals to produce cell-type diversity within the ommatidium. The Hedgehog and Spitz signals are transported along the photoreceptor axons and reused within the brain as long-range and local cues to trigger the differentiation and assembly of target neurons.

Positive Receptor Feedback during Lineage Commitment Can Generate Ultrasensitivity to Ligand and Confer Robustness to a Bistable Switch

Cytokines and lineage-specific transcription factors are critical molecular effectors for terminal differentiation during hematopoiesis. Intrinsic transcription factor activity is often believed to drive commitment and differentiation, whereas cytokine receptor signals have been implicated in the regulation of cell proliferation, survival, and differentiation. In erythropoiesis, recent experimental findings provide direct evidence that erythropoietin (Epo) can generate commitment cues via the erythropoietin receptor (EpoR); specifically, EpoR signaling leads to activation of the transcription factor GATA-1, which then triggers transcription of erythrocyte-specific genes. In particular, activated GATA-1 induces two positive feedback loops in the system through the enhanced expression of both inactive GATA-1 and EpoR, the latter of which is externally regulatable by Epo. Based upon this network architecture, we present a mathematical model of GATA-1 activation by EpoR, which bidirectionally links a lineage-specific receptor and transcription factor. Our deterministic model offers insight into stimulus-response relationships between Epo and several downstream effectors. In addition to the survival signals that EpoR provides, steady-state analysis of our model suggests that receptor upregulation during lineage commitment can also generate ultrasensitivity to Epo and bistability in GATA-1 activity. These system-level properties can induce a switch-like characteristic during differentiation and provide robustness to the mature state. The topology also suggests a novel mechanism for achieving robust bistability in a purely deterministic manner without molecular cooperativity. The analytical solution of a generalized, minimal model is provided and the significance of each of the two positive feedback loops is elucidated through bifurcation analysis. This network topology, or variations thereof, may link other receptor-transcription factor pairs and may therefore be of general relevance in cellular decision-making.

Direct Comparison of G-CSF Receptor and M-CSF Receptor Signaling Leading to AP-1 and STAT Induction and Identification of Novel Signaling Pathways.

External signals often influence developmental decisions. Whether hematopoietic cytokines contribute to lineage specification or serve to amplify decisions made by an intrinsic transcription factor program remains unresolved. Although much is known about signaling events emanating from the G-CSF Receptor (GR) and the M-CSF Receptor (MR), these signals have not been directly compared in a uniform cellular environment. Reasoning that differences seen could contribute to myeloid lineage choice in bipotent cells such as the granulocyte monocyte progenitor (GMP) or the CFU-GM, we have compared GR and MR signaling via endogenous receptors present in the U937 human leukemia cell line and using a subclone derived from the IL-3 dependent Ba/F3 stem cell line expressing both exogenous GR and MR, introduced by retroviral transduction. FACS analysis confirmed that the large majority of cells in our Ba/F3 line express both MR and GR at similarly high levels. Ba/F3 cells were IL-3 starved for 1hr (which caused no change in signaling for the pathways tested) prior to G-CSF, M-CSF stimulation, or mock addition. Both receptors reproducibly activated JNK and induced c-Jun phosphorylation, and both GR and MR signals activated ERK increasing total c-Fos levels, likely via c-Fos serine phosphorylation. Although only the cytoplasmic domain of MR has been demonstrated to interact with PLCγ, two different PLC-inhibitors (U-73122, a PLCγ-specific inhibitor, and edelfosine, a general PLC inhibitor) reduced ERK phosphorylation and c-Fos expression at 30 min downstream of both G-CSF and M-CSF stimulation. A connection between PLCγ and the ERK pathway had not been previously described within these signaling pathways. Two different ERK inhibitors (U0126 and PD9899) reduced c-Fos expression, confirming a link between ERK and c-Fos in hematopoietic cells. PLC and ERK inhibition not only reduced Fos induction, but also increased JNK activation and c-Jun phosphorylation at 30 min, identifying a novel connection between the ERK and JNK branches of the MAPK pathways. Conversely, JNK inhibition with SP600125 reduced c-Jun phosphorylation without altering ERK activation or c-Fos expression. The balance between c-Jun and c-Fos activation via the signaling pathways we have characterized may contribute to granulocyte versus monocyte lineage specification, as exogenous c-Jun directs monocyte development in cooperation with PU.1 and C/EBPα. For example, perhaps increased c-Fos diverts c-Jun to facilitate granulopoiesis. We did not detect differences in the effects of GR or MR on C/EBPα or PU.1 levels, DNA-binding, or C/EBPα serine 21 phosphorylation in U937 or Ba/F3 cells. On the other hand, GR but not MR signals potently induced STAT1, STAT3, and STAT5 tyrosine phosphorylation and DNA-binding at 30 min in Ba/F3 cells, of potential relevance to both proliferation and granulocytic differentiation induced by G-CSF. We now intend to further delineate G-CSF versus M-CSF activation of the JNK/c-Jun, PLCγ/ERK/c-Fos, and STAT pathways and their effects on granulocyte versus monocyte differentiation, using lineage-negative murine myeloid progenitors.

Extrinsic and intrinsic regulation of early natural killer cell development

Natural killer (NK) cells are lymphocytes that play a critical role in both adaptive and innate immune responses. These cells develop from multipotent progenitors in the embryonic thymus and neonatal or adult bone marrow and recent evidence suggests that a subset of these cells may develop in the thymus. Thymus- and bone marrow-derived NK cells have unique phenotypes and functional abilities supporting the hypothesis that the microenvironment dictates the outcome of NK cell development. A detailed understanding of the mechanisms controlling this developmental program will be required to determine how alterations in NK cell development lead to disease and to determine how to harness this developmental program for therapeutic purposes. In this review, we discuss some of the known extrinsic stromal-cell derived factors and cell intrinsic transcription factors that function in guiding NK cell development.

Activation of subventricular zone stem cells after neuronal injury

The mammalian subventricular zone (SVZ) has garnered a tremendous amount of attention as a potential source of replacement cells for neuronal injury. This zone is highly neurogenic, harbours stem cells and supports long-distance migration. The general pattern of activation includes increased proliferation, neurogenesis and emigration towards the injury. Intrinsic transcription factors and environmental signalling molecules are rapidly being discovered that may facilitate the induction of these cells to mount appropriate therapeutic responses. The extent of SVZ neurogenesis in humans is controversial. However, tantalizing new data suggest that humans are capable of generating increased numbers of neurons after a variety of diseases.