p38γ and p38δ modulate innate immune response by regulating MEF2D activation.

Evidence implicating p38γ and p38δ (p38γ/p38δ) in inflammation are mainly based on experiments using -deficient (p38γ/δKO) mice, which show low levels of TPL2, the kinase upstream of MKK1-ERK1/2 in myeloid cells. This could obscure p38γ/p38δ roles, since TPL2 is essential for regulating inflammation. Here, we generated a / (p38γ/δKIKO) mouse, expressing kinase-inactive p38γ and lacking p38δ.

p38δ controls Mitogen- and Stress-activated Kinase-1 (MSK1) function in response to toll-like receptor activation in macrophages.

Mitogen- and Stress-activated Kinase (MSK) 1 is a nuclear protein, activated by p38α Mitogen-Activated Kinase (MAPK) and extracellular signal-regulated kinase (ERK1/2), that modulate the production of certain cytokines in macrophages. Using knockout cells and specific kinase inhibitors, we show that, besides p38α and ERK1/2, another p38MAPK, p38δ, mediates MSK phosphorylation and activation, in LPS-stimulated macrophages. Additionally, recombinant MSK1 was phosphorylated and activated by recombinant p38δ, to the same extent than by p38α, in experiments.

Evolutionary analysis of p38 stress-activated kinases in unicellular relatives of animals suggests an ancestral function in osmotic stress.

p38 kinases are key elements of the cellular stress response in animals. They mediate the cell response to a multitude of stress stimuli, from osmotic shock to inflammation and oncogenes. However, it is unknown how such diversity of function in stress evolved in this kinase subfamily.

4D reconstruction of murine developmental trajectories using spherical harmonics.

Normal organogenesis cannot be recapitulated in vitro for mammalian organs, unlike in species including Drosophila and zebrafish. Available 3D data in the form of ex vivo images only provide discrete snapshots of the development of an organ morphology. Here, we propose a computer-based approach to recreate its continuous evolution in time and space from a set of 3D volumetric images.

TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 with mRNA.

p38γ and p38δ (p38γ/p38δ) regulate inflammation, in part by controlling tumor progression locus 2 (TPL2) expression in myeloid cells. Here, we demonstrate that TPL2 protein levels are dramatically reduced in p38γ/p38δ-deficient (p38γ/δ) cells and tissues without affecting messenger ribonucleic acid (mRNA) expression. We show that p38γ/p38δ posttranscriptionally regulates the TPL2 amount at two different levels.

A Mouse Model of Candidiasis.

The intravenous challenge model of Candida albicans infection in mice is a well-established procedure that mirrors disseminated candidiasis in humans. In this model, in which the fungus is delivered into the bloodstream causing a systemic infection, the kidneys are the primary target organs. Mice develop renal failure and septic shock that recapitulates the progressive sepsis seen in humans during severe clinical cases.

p38 Signalling Pathway.

p38 Mitogen activated protein kinases (p38MAPK) are a highly evolutionary conserved group of protein kinases, which are central for cell adaptation to environmental changes as well as for immune response, inflammation, tissue regeneration, and tumour formation [...

Myeloid cell deficiency of p38γ/p38δ protects against candidiasis and regulates antifungal immunity.

is a frequent aetiologic agent of sepsis associated with high mortality in immunocompromised patients. Developing new antifungal therapies is a medical need due to the low efficiency and resistance to current antifungal drugs. Here, we show that p38γ and p38δ regulate the innate immune response to We describe a new TAK1-TPL2-MKK1-ERK1/2 pathway in macrophages, which is activated by Dectin-1 engagement and positively regulated by p38γ/p38δ.

p38γ and p38δ: From Spectators to Key Physiological Players.

Although the physiological roles of p38γ and p38δ signalling pathways are largely unknown, new genetic and pharmacological tools are providing groundbreaking information on the function of these two stress-activated protein kinases. Recent studies show the importance of p38γ and p38δ in the regulation of processes as diverse as cytokine production, protein synthesis, exocytosis, cell migration, gene expression, and neuron activity, which have an acute impact on the development of pathologies related to inflammation, diabetes, neurodegeneration, and cancer. These recent breakthroughs are resolving some of the questions that have long been asked regarding the function of p38γ and p38δ in biology and pathology.

Arid3b is essential for second heart field cell deployment and heart patterning.

Arid3b, a member of the conserved ARID family of transcription factors, is essential for mouse embryonic development but its precise roles are poorly understood. Here, we show that Arid3b is expressed in the myocardium of the tubular heart and in second heart field progenitors. Arid3b-deficient embryos show cardiac abnormalities, including a notable shortening of the poles, absence of myocardial differentiation and altered patterning of the atrioventricular canal, which also lacks epithelial-to-mesenchymal transition.

Bambi and Sp8 expression mark digit tips and their absence shows that chick wing digits 2 and 3 are truncated.

An often overlooked aspect of digit development is the special nature of the terminal phalanx, a specialized structure with characteristics distinct from other phalanges, for example the presence of ectodermal derivatives such as nails and claws. Here, we describe the unique ossification pattern of distal phalanges and characteristic gene expression in the digit tips of chick and duck embryos. Our results show that the distal phalanx of chick wing digit 1 is a genuine tip with a characteristic ossification pattern and expression of Bambi and Sp8; however, the terminal phalanx of digits 2* and 3 is not a genuine tip, and these are therefore truncated digits.

Apical ectodermal ridge morphogenesis in limb development is controlled by Arid3b-mediated regulation of cell movements.

The apical ectodermal ridge (AER) is a specialized epithelium located at the distal edge of the limb bud that directs outgrowth along the proximodistal axis. Although the molecular basis for its function is well known, the cellular mechanisms that lead to its maturation are not fully understood. Here, we show that Arid3b, a member of the ARID family of transcriptional regulators, is expressed in the AER in mouse and chick embryos, and that interference with its activity leads to aberrant AER development, in which normal structure is not achieved.

Digit morphogenesis: is the tip different?

Digit formation is the last step in the skeletal patterning of developing limbs. This process involves important aspects such as determination of chondrogenic versus interdigital areas; growth of digital rays with periodic segmentation to form joints and thus phalanges, and finally tip formation. Traditionally it was believed that the properties of digital rays were fixed at earlier stages, but recently a surprising plasticity of digit primordia at the time of condensation has been demonstrated.

Manipulations of PKA in chick limb development reveal roles in digit patterning including a positive role in Sonic Hedgehog signaling.

Sonic Hedgehog (Shh) signaling by the polarizing region, at the posterior of the vertebrate limb bud, is pivotal in determining digit number and identity. Shh establishes a gradient of the bifunctional transcriptional effector, Gli3, with high levels of full-length activator (Gli3A) in the posterior bud, where digits form, and high levels of shorter repressor (Gli3R) in the anterior. Repressor formation depends on protein kinase A (PKA), but in Drosophila, PKA also plays a role in activator function.

Fgf signaling controls the number of phalanges and tip formation in developing digits.

Tetrapods have two pairs of limbs, each typically with five digits, each of which has a defined number of phalanges derived from an archetypal formula. Much progress has been made in understanding vertebrate limb initiation and the patterning processes that determine digit number in developing limb buds, but little is known about how phalange number is controlled. We and others previously showed that an additional phalange can be induced in a chick toe if sonic hedgehog protein is applied in between developing digit primordia.

Negative feedback regulation of FGF signaling levels by Pyst1/MKP3 in chick embryos.

Background: The importance of endogenous antagonists in intracellular signal transduction pathways is becoming increasingly recognized. There is evidence in cultured mammalian cells that Pyst1/MKP3, a dual specificity protein phosphatase, specifically binds to and inactivates ERK1/2 mitogen-activated protein kinases (MAPKs). High-level Pyst1/Mkp3 expression has recently been found at many sites of known FGF signaling in mouse embryos, but the significance of this association and its function are not known.

Digital development and morphogenesis.

Signalling interactions between the polarizing region, which produces SHH, and the apical ectodermal ridge, which produces FGFs, are essential for outgrowth and patterning of vertebrate limbs. However, mechanisms that mediate translation of early positional information of cells into anatomy remain largely unknown. In particular, the molecular and cellular basis of digit morphogenesis are not fully understood, either in terms of the formation of the different digits along the antero-posterior axis or in the way digits stop growing once pattern formation has been completed.

Regulation of Tbx3 expression by anteroposterior signalling in vertebrate limb development.

Tbx3, a T-box gene family member related to the Drosophila gene optomotor blind (omb) and encoding a transcription factor, is expressed in anterior and posterior stripes in developing chick limb buds. Tbx3 haploinsufficiency has been linked with the human condition ulnar-mammary syndrome, in which predominantly posterior defects occur in the upper limb. Omb is expressed in Drosophila wing development in response to a signalling cascade involving Hedgehog and Dpp.

"Fingering" the vertebrate limb.

A detailed and precise picture is being pieced together about how the pattern of digits develops in vertebrate limbs. What is particularly exciting is that it will soon be possible to trace the process all the way from establishment of a signalling centre in a small bud of undifferentiated cells right through to final limb anatomy. The development of the vertebrate limb is a traditional model in which to explore mechanisms involved in pattern formation, and there is accelerating knowledge about the genes involved.

PA subunit from influenza virus polymerase complex interacts with a cellular protein with homology to a family of transcriptional activators.

The PA subunit of the influenza virus polymerase complex is a phosphoprotein that induces proteolytic degradation of coexpressed proteins. Point mutants with reduced proteolysis induction reconstitute viral ribonucleoproteins defective in replication but not in transcriptional activity. To look for cellular factors that could associate with PA protein, we have carried out a yeast two-hybrid screen.

Role of FGFs in the control of programmed cell death during limb development.

We have investigated the role of FGFs in the control of programmed cell death during limb development by analyzing the effects of increasing and blocking FGF signaling in the avian limb bud. BMPs are currently considered as the signals responsible for cell death. Here we show that FGF signaling is also necessary for apoptosis and that the establishment of the areas of cell death is regulated by the convergence of FGF- and BMP-mediated signaling pathways.