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Author(s): Haibo Zhang [sup.1] [sup.3] [sup.6], Josef M. Penninger [sup.4] [sup.5], Yimin Li [sup.3], Nanshan Zhong [sup.3], Arthur S. Slutsky [sup.1] [sup.2] [sup.3] Author Affiliations: (1) grid.415502.7, The Keenan Research [...]

Introduction Circulation of blood throughout the cardiovascular system results in biomechanical forces that profoundly influence vessel development and maintenance. Fluid shear stress along the inner lining of blood vessels imparts [...]

Fungal infections constitute a severe health threat, especially to people with an impaired immune status, as observed after HIV infection (1), immune suppression (2), or primary immune deficiencies (3). Candida [...], Fungal infections claim an estimated 1.5 million lives each year. Mechanisms that protect from fungal infections are still elusive. Recognition of fungal pathogens relies on C-type lectin receptors (CLRs) and their downstream signaling kinase SYK. Here we report that the E3 ubiquitin ligase CBLB controls proximal CLR signaling in macrophages and dendritic cells. We show that CBLB associates with SYK and ubiquitinates SYK, dectin-1, and dectin-2 after fungal recognition. Functionally, CBLB deficiency results in increased inflammasome activation, enhanced reactive oxygen species production, and increased fungal killing. Genetic deletion of Cblb protects mice from morbidity caused by cutaneous infection and markedly improves survival after a lethal systemic infection with Candida albicans. On the basis of these findings, we engineered a cell-permeable CBLB inhibitory peptide that protects mice from lethal C. albicans infections. We thus describe a key role for Cblb in the regulation of innate antifungal immunity and establish a novel paradigm for the treatment of fungal sepsis.

Bone-mass regulation depends on the dynamic balance between bone formation and bone resorption, which are driven by osteoblast activation and osteoclast activation, respectively. RANKL is a central positive regulator of [...], Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gaq and GSK3-p signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurindependent 1 (NFATC1) during osteoclastogenesis. Both whole-body ([Lgr4.sup.-/-]) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.

Ectopic expression of transcription factors is sufficient to override stable epigenetic programs and hence alter cell fate (1). For example, forced expression of the pluripotency-related transcription factors Oct4, Klf4, Sox2 [...], Cellular differentiation involves profound remodelling of chromatic landscapes, yet the mechanisms by which somatic cell identity is subsequently maintained remain incompletely understood. To further elucidate regulatory pathways that safeguard the somatic state, we performed two comprehensive RNA interference (RNAi) screens targeting chromatin factors during transcription-factor-mediated reprogramming of mouse fibroblasts to induced pluripotent stem cells (iPS cells). Subunits of the chromatin assembly factor-1 (CAF-1) complex, including Challa and Chaf1b, emerged as the most prominent hits from both screens, followed by modulators of lysine sumoylation and heterochromatin maintenance. Optimal modulation of both CAF-1 and transcription factor levels increased reprogramming efficiency by several orders of magnitude and facilitated iPS cell formation in as little as 4 days. Mechanistically, CAF-1 suppression led to a more accessible chromatin structure at enhancer elements early during reprogramming. These changes were accompanied by a decrease in somatic heterochromatin domains, increased binding of Sox2 to pluripotency-specific targets and activation of associated genes. Notably, suppression of CAF-1 also enhanced the direct conversion of B cells into macrophages and fibroblasts into neurons. Together, our findings reveal the histone chaperone CAF-1 to be a novel regulator of somatic cell identity during transcription-factor-induced cell-fate transitions and provide a potential strategy to modulate cellular plasticity in a regenerative setting.

Genetic ablation of Cbl-b or functional inactivation of its E3 ligase activity in mice results in [CD8.sup.+] T-cell-mediated rejection of primary tumours in several different models (4-6). In a control [...], Tumour metastasis is the primary cause of mortality in cancer patients and remains the key challenge for cancer therapy (1). New therapeutic approaches to block inhibitory pathways of the immune system have renewed hopes for the utility of such therapies (2). Here we show that genetic deletion of the E3 ubiquitin ligase Cbl-b (casitas B-lineage lymphoma-b) or targeted inactivation of its E3 ligase activity licenses natural killer (NK) cells to spontaneously reject metastatic tumours. The TAM tyrosine kinase receptors Tyro3, Axl and Mer (also known as Mertk) were identified as ubiquitylation substrates for Cbl-b. Treatment of wild-type NK cells with a newly developed small molecule TAM kinase inhibitor conferred therapeutic potential, efficiently enhancing anti-metastatic NK cell activity invivo. Oral or intraperitoneal administration using this TAM inhibitor markedly reduced murine mammary cancer and melanoma metastases dependent on NK cells. We further report that the anticoagulant warfarin exerts anti-metastatic activity in mice via Cbl-b/TAM receptors in NK cells, providing a molecular explanation for a 50-year-old puzzle in cancer biology (3). This novel TAM/Cbl-b inhibitory pathway shows that it might be possible to develop a 'pill' that awakens the innate immune system to kill cancer metastases.

Angiotensin converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system (RAS), cata-lyzing the conversion of Angiotensin II to Angiotensin 1-7. Apelin is a second catalytic substrate for [...]

Author(s): Madeline A. Lancaster [sup.1] , Magdalena Renner [sup.1] , Carol-Anne Martin [sup.2] , Daniel Wenzel [sup.1] , Louise S. Bicknell [sup.2] , Matthew E. Hurles [sup.3] , Tessa Homfray [...], The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue. Here the authors present a human pluripotent stem cell-derived three-dimensional organoid culture system that is able to recapitulate several aspects of human brain development in addition to modelling the brain disorder microcephaly, which has been difficult to achieve using mouse models. A model for the human brain Genetically altered mice are used widely to model human diseases, but as the organization of the human brain is so much more complicated than that of a rodent, brain development diseases have not been tackled. Juergen Knoblich and colleagues have developed an alternative model, a three-dimensional organoid culture system, using human pluripotent stem cells, that recapitulates several aspects of human brain development. The system mimics the temporal development of neuronal subtypes and the organization of the tissue into layers. In proof-of-principle experiments the authors produce a microcephaly model using patient-derived induced pluripotent stem cells and describe defects in neuronal differentiation not previously observed in rodent models.

Mammalian brain development begins with the expansion of the neuro-epithelium to generate radial glial stem cells (RGs) (1). These RGs divide at the apical surface within the ventricular zone (VZ) [...], The complexity of the human brain has made it difficult to study many brain disorders in model organisms, highlighting the need for an in vitro model of human brain development. Here we have developed a human pluripotent stem cell-derived three-dimensional organoid culture system, termed cerebral organoids, that develop various discrete, although interdependent, brain regions. These include a cerebral cortex containing progenitor populations that organize and produce mature cortical neuron subtypes. Furthermore, cerebral organoids are shown to recapitulate features of human cortical development, namely characteristic progenitor zone organization with abundant outer radial glial stem cells. Finally, we use RNA interference and patient-specific induced pluripotent stem cells to model microcephaly, a disorder that has been difficult to recapitulate in mice. We demonstrate premature neuronal differentiation in patient organoids, a defect that could help to explain the disease phenotype. Together, these data show that three-dimensional organoids can recapitulate development and disease even in this most complex human tissue.

RNA molecules undergo co- and post-transcriptional processing, leading to mature, functional RNAs. In mammals and archaea CLP1 proteins are kinases that phosphorylate the 5' hydroxyl ends of RNA (1-3). Human [...], CLP1 was the first mammalian RNA kinase to be identified. However, determining its in vivo function has been elusive. Here we generated kinase-dead Clpl ([Clp1.sup.K/K]) mice that show a progressive loss of spinal motor neurons associated with axonal degeneration in the peripheral nerves and denervation of neuromuscular junctions, resulting in impaired motor function, muscle weakness, paralysis and fatal respiratory failure. Transgenic rescue experiments show that CLP1 functions in motor neurons. Mechanistically, loss of CLP1 activity results in accumulation of a novel set of small RNA fragments, derived from aberrant processing of tyrosine pre-transfer RNA. These tRNA fragments sensitize cells to oxidative-stress-induced p53 (also known as TRP53) activation and p53-dependent cell death. Genetic inactivation of p53 rescues [Clp1.sup.K/K] mice from the motor neuron loss, muscle denervation and respiratory failure. Our experiments uncover a mechanistic link between tRNA processing, formation of a new RNA species and progressive loss of lower motor neurons regulated by p53.

RANKL (also known as TNFSF11) is a member of the tumor necrosis factor superfamily and, after ligation with its cognate receptor RANK (also known as TNFRSF11a), is a potent stimulator [...], Hepatic insulin resistance is a driving force in the pathogenesis of type 2 diabetes mellitus (T2DM) and is tightly coupled with excessive storage of fat and the ensuing inflammation within the liver (1-3). There is compelling evidence that activation of the transcription factor nuclear factor-κB (NF-κB) and downstream inflammatory signaling pathways systemically and in the liver are key events in the etiology of hepatic insulin resistance and b-cell dysfunction, although the molecular mechanisms involved are incompletely understood (3-6). We here test the hypothesis that receptor activator of NF-κB ligand (RANKL), a prototypic activator of NF-κB, contributes to this process using both an epidemiological and experimental approach. In the prospective population-based Bruneck Study, a high serum concentration of soluble RANKL emerged as a significant (P < 0.001) and independent risk predictor of T2DM manifestation. In close agreement, systemic or hepatic blockage of RANKL signaling in genetic and nutritional mouse models of T2DM resulted in a marked improvement of hepatic insulin sensitivity and amelioration or even normalization of plasma glucose concentrations and glucose tolerance. Overall, this study provides evidence for a role of RANKL signaling in the pathogenesis of T2DM. If so, translation to the clinic may be feasible given current pharmacological strategies to lower RANKL activity to treat osteoporosis.

ALCLs are T cell lymphomas (1), (2) comprising 10-20% of all non-Hodgkin's lymphoma cases in children and 3% in adults (3). About half of ALCL cases are positive for the [...], Anaplastic large cell lymphoma (ALCL) is an aggressive non-Hodgkin's lymphoma found in children and young adults. ALCLs frequently carry a chromosomal translocation that results in expression of the oncoprotein nucleophosmin--anaplastic lymphoma kinase (NPM-ALK). The key molecular downstream events required for NPM-ALK--triggered lymphoma growth have been only partly unveiled. Here we show that the activator protein 1 family members JUN and JUNB promote lymphoma development and tumor dissemination through transcriptional regulation of platelet-derived growth factor receptor-β (PDGFRB) in a mouse model of NPM-ALK-triggered lymphomagenesis. Therapeutic inhibition of PDGFRB markedly prolonged survival of NPM-ALK transgenic mice and increased the efficacy of an ALK-specific inhibitor in transplanted NPM-ALK tumors. Notably, inhibition of PDGFRA and PDGFRB in a patient with refractory late-stage NPM-[ALK.sup.+] ALCL resulted in rapid, complete and sustained remission. Together, our data identify PDGFRB as a previously unknown JUN and JUNB target that could be a highly effective therapy for ALCL.

Malnutrition affects up to one billion people in the world and is a major cause of mortality (1,2). In many cases malnutrition is associated with diarrhoea and intestinal inflammation, further [...]

In vitro osteoclast differentiation is induced by the cell-cell contact between osteoclast precursor cells of the monocyte/macrophage lineage and anchorage-dependent mesenchymal cells in bone, which include osteoblasts and bone marrow [...], Osteocytes embedded in bone have been postulated to orchestrate bone homeostasis by regulating both bone-forming osteoblasts and bone-resorbing osteoclasts. We find here that purified osteocytes express a much higher amount of receptor activator of nuclear factor-κB ligand (RANKL) and have a greater capacity to support osteoclastogenesis in vitro than osteoblasts and bone marrow stromal cells. Furthermore, the severe osteopetrotic phenotype that we observe in mice lacking RANKL specifically in osteocytes indicates that osteocytes are the major source of RANKL in bone remodeling in vivo.

RANKL (also known as ODF, TRANCE, OPGL and TNFSF11) and its receptor RANK (also known as TRANCE-R and TNFRSF11A) are essential for the development and activation of osteoclasts (4,5). The [...], Breast cancer is one of the most common cancers in humans and will on average affect up to one in eight women in their lifetime in the United States and Europe (1). The Women's Health Initiative and the Million Women Study have shown that hormone replacement therapy is associated with an increased risk of incident and fatal breast cancer (2,3). In particular, synthetic progesterone derivatives (progestins) such as medroxyprogesterone acetate (MPA), used in millions of women for hormone replacement therapy and contraceptives, markedly increase the risk of developing breast cancer. Here we show that the invivoadministration of MPA triggers massive induction of the key osteoclast differentiation factor RANKL (receptor activator of NF-κB ligand) in mammary-gland epithelial cells. Genetic inactivation of the RANKL receptor RANK in mammary-gland epithelial cells prevents MPA-induced epithelial proliferation, impairs expansion of the [CD49f.sup.hi] stem-cell-enriched population, and sensitizes these cells to DNA-damage-induced cell death. Deletion of RANK from the mammary epithelium results in a markedly decreased incidence and delayed onset of MPA-driven mammary cancer. These data show that the RANKL/RANK system controls the incidence and onset of progestin-driven breast cancer.

Introduction Common mutational processes underpin the development of diverse cancers by perturbing key regulatory networks that have evolved to resist the emergence of neoplastic cells in normal tissues. Some human [...], Some cancers have been stratified into subclasses based on their unique involvement of specific signaling pathways. The mapping of human cancer genomes is revealing a vast number of somatic alterations; however, the identification of clinically relevant molecular tumor subclasses and their respective driver genes presents challenges. This information is key to developing more targeted and personalized cancer therapies. Here, we generate a new mouse model of genomically unstable osteosarcoma (OSA) that phenocopies the human disease. Integrative oncogenomics pinpointed cAMP-dependent protein kinase type I, α regulatory subunit (Prkar1a) gene deletions at 11qE1 as a recurrent genetic trait for a molecularly distinct subclass of mouse OSA featuring RANKL overexpression. Using mouse genetics, we established that Prkar1a is a bone tumor suppressor gene capable of directing subclass development and driving RANKL overexpression during OSA tumorigenesis. Finally, we uncovered evidence for a PRKAR1A-low subset of human OSA with distinct clinical behavior. Thus, tumor subclasses develop in mice and can potentially provide information toward the molecular stratification of human cancers.

Tumor necrosis factor (TNF) is an inflammatory cytokine that is upregulated in a number of cardiomyopathies. Adverse cardiac remodeling and dilation result from degradation of the extracellular matrix by matrix metalloproteinases (MMPs). We investigated whether TNF can directly trigger expression and activation of MMPs in cardiac cells. We compared MMP expression profile and activities between primary cultures of mouse neonatal cardiomyocytes and cardiofibroblasts and in cellular and extracellular compartments. In response to recombinant TNF (rTNF, 20 ng/ml), cardiomyocytes exhibited faster and more pronounced superoxide production compared with cardiofibroblasts, concomitant with increased expression of several MMPs. MMP9 levels increased more rapidly and about twofold more in cardiomyocytes than in cardiofibroblasts. TNF did not induce MMP2 expression. Expression of collagenases (MMP8, MMP12, MMP13, and MMP14) increased significantly, while total collagenase activity increased to a greater degree in conditioned medium of cardiomyocytes than in cardiofibroblasts, rTNF-mediated MMP expression and activation were dependent on superoxide production and were blocked by apocynin, an NADPH oxidase inhibitor. We identified phosphatidylinositol 3-kinase (PI3K)[gamma] as a key factor in TNF-mediated events since TNF-induced superoxide production, MMP expression, and activity were significantly suppressed in cardiomyocytes and cardiofibroblasts deficient in PI3K[gamma]. We further demonstrated that the TNF-superoxide-MMP axis of events is in fact activated in heart disease in vivo. Wild-type and [TNF.sup.-/-] mice subjected to cardiac pressure overload revealed that TNF deficiency resulted in reduced superoxide levels, collagenase activities, PI3K activity, and fibrosis leading to attenuated cardiac dilation and dysfunction. Our study demonstrates that TNF triggers expression and activation of MMPs faster and stronger in cardiomyocytes than in cardiofibroblasts in a superoxide-dependent manner and via activation of PI3K[gamma], thereby contributing to adverse myocardial remodeling in disease. reactive oxygen species; NADPH oxidase; pressure overload doi:10.1152/ajpcell.00351.2009.

Innate immunity represents the first line of defense in animals. We report a genome-wide in vivo Drosophila RNA interference screen to uncover genes involved in susceptibility or resistance to intestinal infection with the bacterium Serratia marcescens. We first employed whole-organism gene suppression, followed by tissue-specific silencing in gut epithelium or hemocytes to identify several hundred genes involved in intestinal antibacterial immunity. Among the pathways identified, we showed that the JAK-STAT signaling pathway controls host defense in the gut by regulating stem cell proliferation and thus epithelial ceil homeostasis. Therefore, we revealed multiple genes involved in antibacterial defense and the regulation of innate immunity.

Osteoclasts are multinucleated cells that resorb bone. Although osteoclasts originate from the monocyte/macrophage lineage, osteoclast precursors are not well characterized in vivo. The relationship between proliferation and differentiation of osteoclast precursors is examined in this study using murine macrophage cultures treated with macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-[kappa]B (RANK) ligand (RANKL). Cell cycle-arrested quiescent osteoclast precursors (QuOPs) were identified as the committed osteoclast precursors in vitro. In vivo experiments show that QuOPs survive for several weeks and differentiate into osteoclasts in response to M-CSF and RANKL. Administration of 5-fluorouracil to mice induces myelosuppression, but QuOPs survive and differentiate into osteoclasts in response to an active vitamin D3 analogue given to those mice. Mononuclear cells expressing c-Fms and RANK but not Ki67 are detected along bone surfaces in the vicinity of osteoblasts in RANKL-deficient mice. These results suggest that QuOPs preexist at the site of osteoclastogenesis and that osteoblasts are important for maintenance of QuOPs.

The endothelium plays a central role in the maintenance of vascular homeostasis. One of the main effectors of endothelial dysfunction is ANG II, and pharmacological approaches to limit ANG II bioactivity remain the cornerstone of cardiovascular therapeutics. Angiotensin converting enzyme-2 (ACE2) has been identified as a critical negative modulator of ANG II bioactivity, counterbalancing the effects of ACE in determining net tissue ANG II levels; however, the role of ACE2 in the vasculature remains unknown. In the present study, we hypothesized that ACE2 is a novel target to limit endothelial dysfunction and atherosclerosis. To this aim, we performed in vitro gain and loss of function experiments in endothelial cells and evaluated in vivo angiogenesis and atherosclerosis in apolipoprotein E-knockout mice treated with AdACE2. ACE2-deficient mice exhibited impaired endothelium-dependent relaxation. Overexpression of ACE2 in human endothelial cells stimulated endothelial cell migration and tube formation, and limited monocyte and cellular adhesion molecule expression; effects that were reversed in ACE2 gene silenced and endothelial cells isolated from ACE2-deficient animals. ACE2 attenuated ANG H-induced reactive oxygen species production in part through decreasing the expression of p22phox. The effects of ACE2 on endothelial activation were attenuated by pharmacological blockade of ANG-(1-7) with A779. ACE2 promoted capillary formation and neovessel maturation in vivo and reduced atherosclerosis in apolipoprotein E-knockout mice These data indicate that ACE2, in an ANG-(1-7)-dependent fashion, functions to improve endothelial homeostasis via a mechanism that may involve attenuation of NADPHox-induced reactive oxygen species production. ACE2-based treatment approaches may be a novel approach to limit aberrant vascular responses and atherothrombosis. endothelium; atherogenesis; angiogenesis

Author(s): Ulrich Elling (corresponding author) [1]; Reiner A. Wimmer [1]; Andreas Leibbrandt [1]; Thomas Burkard [1]; Georg Michlits [1]; Alexandra Leopoldi [1]; Thomas Micheler [2]; Dana Abdeen [1]; Sergei Zhuk [...]

Author(s): Johannes Stadlmann [1]; Jasmin Taubenschmid [1]; Daniel Wenzel [1]; Anna Gattinger [1, 2]; Gerhard Drnberger [1, 2, 3]; Frederico Dusberger [2]; Ulrich Elling [1]; Lukas Mach [4]; Karl Mechtler [...]

Author(s): Liyong Zhang [1, 2, 5]; Michael S Anglesio [3, 5]; Maureen O'Sullivan [3]; Fan Zhang [3]; Ge Yang [2]; Renu Sarao [1, 2]; Mai P Nghiem [1, 2]; Shane [...]

Platelets are critical for normal hemostasis. Their deregulation can lead to bleeding or to arterial thrombosis, a primary cause of heart attack and ischemic stroke. Src homology 2 domain--containing inositol [...]

Author(s): Karin Loser [1, 2]; Annette Mehling [1]; Stefanie Loeser [3]; Jenny Apelt [1]; Annegret Kuhn [4]; Stephan Grabbe [5]; Thomas Schwarz [6]; Josef M Penninger [3]; Stefan Beissert (corresponding [...]

Author(s): Min Zhao (corresponding author) [1]; Bing Song [1]; Jin Pu [1]; Teiji Wada [2]; Brian Reid [1]; Guangping Tai [1]; Fei Wang [3, 7]; Aihua Guo [1]; Petr Walczysko [...]

Apoptosis-inducing factor (AIF) is an evolutionarily conserved, ubiquitously expressed flavoprotein with NADH oxidase activity that is normally confined to mitochondria. In mammalian cells, AIF is released from mitochondria in response to apoptotic stimuli and translocates to the nucleus where it is thought to bind DNA and contribute to chromatinolysis and cell death in a caspase-independent manner. Here we describe the consequences of inactivating Aif in the early mouse embryo. Unexpectedly, we found that both the apoptosis-dependent process of cavitation in embryoid bodies and apoptosis associated with embryonic neural tube closure occur in the absence of AIF, indicating that Aif function is not required for apoptotic cell death in early mouse embryos. By embryonic day 9 (E9), loss of Aif function causes abnormal cell death, presumably because of reduced mitochondrial respiratory chain complex I activity. Because of this cell death, Aif null embryos fail to increase significantly in size after E9. Remarkably, patterning processes continue on an essentially normal schedule, such that E10 Aif null embryos with only [approximately equal to] 1/10 the normal number of cells have the same somite number as their wild-type littermates. These observations show that pattern formation in the mouse can occur independent of embryo size and cell number. apoptosis | cavitation | embyro patterning | somitogenesis | mitochondrial respiratory chain complex |

The purpose of the mammary gland is to provide the newborn with coplous amounts of milk, a unique body fluid that has a dual role of nutrition and immunological protection. The results postulated that mammary glands evolved from the innate immune system as xanthine oxidoreductase evolved a dual role in the mammary gland and hence provide new evidence supporting the hypothesis that the nutritional function of the milk evolved subsequent to its protective function.

Author(s): D. Holstead Jones [1, 2, 3, 11, 10]; Tomoki Nakashima [1, 11]; Otto H. Sanchez [4, 10]; Ivona Kozieradzki [1, 2, 3]; Svetlana V. Komarova [5]; Ildiko Sarosi [6]; [...]

Author(s): Keiji Kuba [1, 7]; Yumiko Imai [1, 7]; Shuan Rao [2, 7]; Hong Gao [3]; Feng Guo [2]; Bin Guan [2]; Yi Huan [2]; Peng Yang [2]; Yanli Zhang [...]

Author(s): Yumiko Imai [1, 10]; Keiji Kuba [1, 10]; Shuan Rao [2]; Yi Huan [2]; Feng Guo [2]; Bin Guan [2]; Peng Yang [2]; Renu Sarao [1]; Teiji Wada [1]; [...]

Author(s): Teiji Wada (corresponding author) [1]; Tomoki Nakashima [1]; Antonio J Oliveira-dos-Santos [2]; Juerg Gasser [3]; Hiromitsu Hara [1]; Georg Schett [4]; Josef M Penninger (corresponding author) [1] The accumulation [...]

Cardiac hypertrophic stimuli induce both adaptive and maladaptive growth response pathways in heart. A study showing that the mice lacking junD develop less adaptive hypertrophy in heart after mechanical pressure overload, while cardiomyocyte-specific expression of junD in mice results in spontaneous ventricular dilation and decreased contractility is detailed.

Author(s): Matthew A Gronski [1]; Jonathan M Boulter [2]; Demetrius Moskophidis [3]; Linh T Nguyen [1]; Kaisa Holmberg [4]; Alisha R Elford [1]; Elissa K Deenick [1]; Hee O Kim [...]

Author(s): Urs Eriksson (corresponding author) [1, 2]; Romeo Ricci [1]; Lukas Hunziker [2]; Michael O Kurrer [3]; Gavin Y Oudit [4]; Tania H Watts [5]; Ivo Sonderegger [6]; Kurt Bachmaier [...]

Meiosis is a fundamental process in sexually reproducing species that allows genetic exchange between maternal and paternal genomes (1, 2). Defects in high-fidelity meiotic chromosome alignment or in genome segregation [...], Meiosis is a critical stage of gametogenesis in which alignment and synapsis of chromosomal pairs occur, allowing for the recombination of maternal and paternal genomes. Here we show that FK506 binding protein (Fkbp6) localizes to meiotic chromosome cores and regions of homologous chromosome synapsis. Targeted inactivation of Fkbp6 in mice results in aspermic males and the absence of normal pachytene spermatocytes. Moreover, we identified the deletion of Fkbp6 exon 8 as the causative mutation in spontaneously male sterile as/as mutant rats. Loss of Fkbp6 results in abnormal pairing and misalignments between homologous chromosomes, nonhomologous partner switches, and autosynapsis of X chromosome cores in meiotic spermatocytes. Fertility and meiosis are normal in Fkbp6 mutant females. Thus, Fkbp6 is a component of the synaptonemal complex essential for sex-specific fertility and for the fidelity of homologous chromosome pairing in meiosis.

Mice lacking the stress-signaling kinase SEK1 die from embryonic day 10.5 (E10.5) to E12.5. Although a defect in liver formation is accompanied with the embryonic lethality of sek[1.sup.-/-] mice, the mechanism of the liver defect has remained unknown. In the present study, we first produced a monoclonal antibody specifically recognizing murine hepatoblasts for the analysis of liver development and further investigated genetic interaction of sek1 with tumor necrosis factor-[alpha] receptor 1 gene (tnfr1) and protooncogene c-jun, which are also responsible for liver formation and cell apoptosis. The defective liver formation in sek[1.sup.-/-] embryos was not protected by additional tnfr1 mutation, which rescues the embryonic lethality of mice lacking NF-[kappa]B signaling components. There was a progressive increase in the hepatoblast cell numbers of wild-type embryos from E10.5 to E12.5. Instead, impaired hepatoblast proliferation was observed in sek[1.sup.-/-] livers from E10.5, though fetal liver-specific gene expression was normal. The impaired phenotype in sek[1.sup.-/-] livers was more severe than in [c-jun.sup.-/-] embryos, and sek[1.sup.-/-] [c-jun.sup.-/-] embryos died more rapidly before E8.5. The hepatoblast proliferation required no hematopoiesis, since liver development was not impaired in AML[1.sup.-/-] mice that lack hematopoietic functions. Stimulation of stress-activated protein kinase/c-Jun N-terminal kinase by hepatocyte growth factor was attenuated in sek[1.sup.-/-] livers. Thus, SEK1 appears to play a crucial role in hepatoblast proliferation and survival in a manner apparently different from NF-[kappa]B or c-Jun. Key words: SEK1; NF-[kappa]B; c-Jun; HGF; hematopoiesis; hepatogenesis.

Research has been conducted on the PI3K/PTEN signaling pathways. The study of cardiomycete-specific inactivation of tumor suppressor PTEN leading to cardiac contractility disease has been carried out and the role of PTEN in cardiomyocyte hypertrophy and GPCR signaling and the functions of PI3K/PTEN pathway in heart muscle contractility modulation are discussed.

Author(s): Michael A. Crackower [1, 2, 3]; Renu Sarao [1, 4, 5]; Gavin Y. Oudit [3, 5, 6, 7]; Chana Yagil [8]; Ivona Kozieradzki [1, 4]; Sam E. Scanga [9]; [...]

Author(s): Nobutaka Suzuki [1, 2]; Shinobu Suzuki [1, 2]; Gordon S. Duncan [1]; Douglas G. Millar [3]; Teiji Wada [1]; Christine Mirtsos [1]; Hidetoshi Takada [1]; Andrew Wakeham [1]; Annick [...]

Results demonstrate that the calcium-sensing protein DREAM is involved in pain processing. Mutants lacking this protein respond poorly to acute thermal, mechanical, and visceral pain as well as to chronic neuropathic and inflammatory pain.

Author(s): Nicholas Joza [1, 2]; Santos A. Susin [3]; Eric Daugas [3, 4]; William L. Stanford [5]; Sarah K. Cho [2]; Carol Y. J. Li [5]; Takehiko Sasaki [1, 6]; [...]

Author(s): Junko Irie-Sasaki [1, 2, 3]; Takehiko Sasaki (corresponding author) [1, 2, 3]; Wataru Matsumoto [4]; Anne Opavsky [5]; Mary Cheng [1]; Grant Welstead [1]; Emily Griffiths [1]; Connie Krawczyk [...]

Author(s): Anna Tafuri [1, 2, 3]; Arda Shahinian [1, 2, 3]; Friedhelm Bladt [1, 4]; Steve K. Yoshinaga [5]; Manel Jordana [6]; Andrew Wakeham [2, 3]; Louis-Martin Boucher [2, 3]; [...]

The osteoclast differentiation factor osteoprotegerin-ligand (OPGL), essential for bone remodeling, has been found to be required for mammary gland development. Mice that have no OPGL or lack its receptor RANK fail to form lobulo-alveolar mammary structures in pregnancy, resulting in death of newborns. The data give a novel paradigm in mammary gland development and give a rationale related to evolution for hormonal regulation and gender bias for female osteoporosis.

Author(s): Takehiko Sasaki [1]; Junko Irie-Sasaki [1]; Yasuo Horie; Kurt Bachmaier [1]; Jimmie E. Fata [2]; Martin Li [3]; Akira Suzuki [1]; Dennis Bouchard [1]; Alexandra Ho [1]; Mark Redston [...]

Author(s): Peter Liu [1]; Karen Aitken [1]; Young-Yun Kong [2]; Mary Anne Opavsky [1]; Tammy Martino [1]; Fayez Dawood [1]; Wen-Hu Wen [1]; Ivona Kozieradzki [2]; Kurt Bachmaier [2]; David [...]

Author(s): Kurt Bachmaier [1]; Connie Krawczyk [1]; Ivona Kozieradzki [1]; Young-Yun Kong [1]; Takehiko Sasaki [1]; Antonio Oliveira-dos-Santos [1]; Sanjeev Mariathasan [2]; Dennis Bouchard [1]; Andrew Wakeham [1]; Annick Itie [...]