Heterozygous variants disrupting the interaction of ERF with activated ERK1/2 cause microcephaly, developmental delay, and skeletal anomalies.

Heterozygous deleterious null alleles and specific missense variants in the DNA-binding domain of the ETS2 repressor factor (ERF) cause craniosynostosis, while the recurrent p.(Tyr89Cys) missense variant is associated with Chitayat syndrome. Exome and whole transcriptome sequencing revealed the ERF de novo in-frame indel c.

scRNA-Explorer: An End-user Online Tool for Single Cell RNA-seq Data Analysis Featuring Gene Correlation and Data Filtering.

In the majority of downstream analysis pipelines for single-cell RNA sequencing (scRNA-seq), techniques like dimensionality reduction and feature selection are employed to address the problem of high-dimensional nature of the data. These approaches involve mapping the data onto a lower-dimensional space, eliminating less informative genes, and pinpointing the most pertinent features. This process ultimately leads to a reduction in the number of dimensions used for downstream analysis, which in turn speeds up the computation of large-scale scRNA-seq data.

Development of Erf-Mediated Craniosynostosis and Pharmacological Amelioration.

ETS2 repressor factor () insufficiency causes craniosynostosis (CRS4) in humans and mice. ERF is an ETS domain transcriptional repressor regulated by Erk1/2 phosphorylation via nucleo-cytoplasmic shuttling. Here, we analyze the onset and development of the craniosynostosis phenotype in an Erf-insufficient mouse model and evaluate the potential of the residual Erf activity augmented by pharmacological compounds to ameliorate the disease.

ETS2 repressor factor (ERF) is involved in T lymphocyte maturation acting as regulator of thymocyte lineage commitment.

Thymocyte differentiation and lineage commitment is regulated by an extensive network of transcription factors and signaling molecules among which Erk plays a central role. However, Erk effectors as well as the molecular mechanisms underlying this network are not well understood. Erf is a ubiquitously expressed transcriptional repressor regulated by Erk-dependent phosphorylation.

Micro-CT for Biological and Biomedical Studies: A Comparison of Imaging Techniques.

Several imaging techniques are used in biological and biomedical studies. Micro-computed tomography (micro-CT) is a non-destructive imaging technique that allows the rapid digitisation of internal and external structures of a sample in three dimensions and with great resolution. In this review, the strengths and weaknesses of some common imaging techniques applied in biological and biomedical fields, such as optical microscopy, confocal laser scanning microscopy, and scanning electron microscopy, are presented and compared with the micro-CT technique through five use cases.

Erf Affects Commitment and Differentiation of Osteoprogenitor Cells in Cranial Sutures via the Retinoic Acid Pathway.

ETS2 repressor factor (ERF) haploinsufficiency causes late-onset craniosynostosis (CRS) (OMIM entry 600775; CRS4) in humans, while in mice Erf insufficiency also leads to a similar multisuture synostosis phenotype preceded by mildly reduced calvarium ossification. However, neither the cell types affected nor the effects have been identified so far. Here, we establish an system for the expansion of suture-derived mesenchymal stem and progenitor cells (sdMSCs) and analyze the role of Erf levels in their differentiation.

Craniofacial, orofacial and dental disorders: the role of the RAS/ERK pathway.

Deviations from the precisely coordinated programme of human head development can lead to craniofacial and orofacial malformations often including a variety of dental abnormalities too. Although the aetiology is still unknown in many cases, during the last decades different intracellular signalling pathways have been genetically linked to specific disorders. Among these pathways, the RAS/extracellular signal-regulated kinase (ERK) signalling cascade is the focus of this review since it encompasses a large group of genes that when mutated cause some of the most common and severe developmental anomalies in humans.

The Ets2 Repressor Factor (Erf) Is Required for Effective Primitive and Definitive Hematopoiesis.

is a gene for a ubiquitously expressed Ets DNA-binding domain-containing transcriptional repressor. haploinsufficiency causes craniosynostosis in humans and mice, while its absence in mice leads to failed chorioallantoic fusion and death at embryonic day 10.5 (E10.

Suppression of Fgf2 by ETS2 repressor factor (ERF) is required for chorionic trophoblast differentiation.

ETS2 repressor factor (ERF) is a ubiquitous transcriptional repressor regulated by Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation. Homozygous deletion of Erf in mice blocks chorionic trophoblast differentiation, resulting in the failure of chorioallantoic fusion and subsequent embryo death. Fibroblast growth factor (FGF) signaling is important for proper trophoblast stem cell (TSC) differentiation and development of the hemochorial placenta.

Reduced dosage of ERF causes complex craniosynostosis in humans and mice and links ERK1/2 signaling to regulation of osteogenesis.

The extracellular signal-related kinases 1 and 2 (ERK1/2) are key proteins mediating mitogen-activated protein kinase signaling downstream of RAS: phosphorylation of ERK1/2 leads to nuclear uptake and modulation of multiple targets. Here, we show that reduced dosage of ERF, which encodes an inhibitory ETS transcription factor directly bound by ERK1/2 (refs. 2,3,4,5,6,7), causes complex craniosynostosis (premature fusion of the cranial sutures) in humans and mice.

Semaphorin-7a reverses the ERF-induced inhibition of EMT in Ras-dependent mouse mammary epithelial cells.

Epithelial-to-mesenchymal transition (EMT) is a key process in cancer progression and metastasis, requiring cooperation of the epidermal growth factor/Ras with the transforming growth factor-β (TGF-β) signaling pathway in a multistep process. The molecular mechanisms by which Ras signaling contributes to EMT, however, remain elusive to a large extent. We therefore examined the transcriptional repressor Ets2-repressor factor (ERF)-a bona fide Ras-extracellular signal-regulated kinase/mitogen-activated protein kinase effector-for its ability to interfere with TGF-β-induced EMT in mammary epithelial cells (EpH4) expressing oncogenic Ras (EpRas).

Calcium/calmodulin-dependent protein kinase II regulates IL-10 production by human T lymphocytes: a distinct target in the calcium dependent pathway.

Calcium (Ca2+) plays an essential role in lymphocyte activation and differentiation by affecting signaling pathways leading to cytokine production. Among the enzymes responding to calcium increase, Ca2+/calmodulin-dependent protein kinase II (CaMKII) has been involved in anergy with a still poorly characterized role. IL-10 produced by different T lymphocyte subpopulations is critical mediator of tolerance.

EGR1 and the ERK-ERF axis drive mammary cell migration in response to EGF.

The signaling pathways that commit cells to migration are incompletely understood. We employed human mammary cells and two stimuli: epidermal growth factor (EGF), which induced cellular migration, and serum factors, which stimulated cell growth. In addition to strong activation of ERK by EGF, and AKT by serum, early transcription remarkably differed: while EGF induced early growth response-1 (EGR1), and this was required for migration, serum induced c-Fos and FosB to enhance proliferation.

cAMP regulates IL-10 production by normal human T lymphocytes at multiple levels: a potential role for MEF2.

Signal transduction by the cAMP/cAMP-dependent protein kinase A (PKA) pathway is triggered through multiple receptors and is important for many processes in a variety of cells. In T cells, the engagement of the TCR-CD3 complex induces cAMP, a second messenger that controls immune response. IL-10, produced by a variety of lymphocyte subpopulations, is an important regulator of this response exerting a wide range of immunomodulatory actions.

Ets2 is required for trophoblast stem cell self-renewal.

The Ets2 transcription factor is essential for the development of the mouse placenta and for generating signals for embryonic mesoderm and axis formation. Using a conditional targeted Ets2 allele, we show that Ets2 is essential for trophoblast stem (TS) cells self-renewal. Inactivation of Ets2 results in TS cell slower growth, increased expression of a subset of differentiation-associated genes and decreased expression of several genes implicated in TS self-renewal.

The RAS-dependent ERF control of cell proliferation and differentiation is mediated by c-Myc repression.

The ERF transcriptional repressor is a downstream effector of the RAS/ERK pathway that interacts with and is directly phosphorylated by ERKs in vivo and in vitro. This phosphorylation results in its cytoplasmic export and inactivation, although lack of ERK activity allows its immediate nuclear accumulation and repressor function. Nuclear ERFs arrest cell cycle progression in G(1) and can suppress ras-dependent tumorigenicity.

Transcriptional repressor erf determines extraembryonic ectoderm differentiation.

Extraembryonic ectoderm differentiation and chorioallantoic attachment are fibroblast growth factor (FGF)- and transforming growth factor beta-regulated processes that are the first steps in the development of the placenta labyrinth and the establishment of the fetal-maternal circulation in the developing embryo. Only a small number of genes have been demonstrated to be important in trophoblast stem cell differentiation. Erf is a ubiquitously expressed Erk-regulated, ets domain transcriptional repressor expressed throughout embryonic development and adulthood.

The transcriptional ETS2 repressor factor associates with active and inactive Erks through distinct FXF motifs.

The transcriptional ETS2 repressor factor (ERF) is phosphorylated by Erks both in vivo and in vitro. This phosphorylation determines the subcellular localization and biological function of ERF. Here, we show that active and inactive Erk2 proteins bind ERF with high affinity through a hydrophobic pocket formed by the alphaF and alphaG helices and the activation loop of Erk2.

Conditional up-regulation of IL-2 production by p38 MAPK inactivation is mediated by increased Erk1/2 activity.

The p38 mitogen-activated protein kinase regulates many cellular processes in almost all eukaryotic cell types. In T cells, p38 was shown to regulate thymic development and cytokine production. Here, the role of p38 on interleukin-2 (IL-2) production by human peripheral blood CD4+ T cells was examined.

IL-2 and IL-10 production by human CD4+T cells is differentially regulated by p38: mode of stimulation-dependent regulation of IL-2.

Antigenic stimulation of T cells initiates a complex series of intracellular signaling pathways that target and activate different cytokine genes. The participation of mitogen-activated protein kinases (MAPKs) in these processes has not been studied thoroughly and in some instances conflicting results have been reported. Here we have examined the role of p38 MAPK on IL-2 and IL-10 production following activation of human CD4+ T cells or of the leukemic cell line Hut-78, with either plate-bound anti-CD3 in the presence or absence of soluble anti-CD28 (plCD3, plCD3/sCD28), or with cross-linked anti-CD3 and anti-CD28 (crsCD3+CD28), or with PMA plus ionomycin.

ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression.

The ets domain transcriptional repressor ERF is an effector of the receptor tyrosine kinase/Ras/Erk pathway, which, it has been suggested, is regulated by subcellular localization as a result of Erk-dependent phosphorylation and is capable of suppressing cell proliferation and ras-induced tumorigenicity. Here, we analyze the effect of ERF phosphorylation on nuclear import and export, the timing of its phosphorylation and dephosphorylation in relation to its subcellular location, Erk activity, and the requirements for ERF-induced cell cycle arrest. Our findings indicate that ERF continuously shuttles between the nucleus and the cytoplasm and that both phosphorylation and dephosphorylation of ERF occur within the nucleus.

ERF, an ETS-related transcriptional repressor, can induce erythroid differentiation.

Ets-family genes have been implicated in leukemia, as well as in normal hematopoiesis. ERF is an ets-related gene that represses transcription and is regulated by MAPK phosphorylation through its effect on ERF sub-cellular localization. Using pluripotent human cell lines, we studied the effect of ERF on erythroid differentiation.