The multiple signaling modalities of adhesion G protein-coupled receptor GPR126 in development

The G protein-coupled receptor (GPCR) superfamily is the largest known receptor family in the human genome. Although the family of adhesion GPCRs comprises the second largest sub-family, their function is poorly understood. Here, we review the current knowledge about the adhesion GPCR family member GPR126. GPR126 possesses a signal peptide, a 7TM domain homologous to secretin-like GPCRs, a GPS motif and an extended N-terminus containing a CUB (Complement, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a hormone binding domain and 27 putative N-glycosylation sites. Knockdown and knockout experiments in zebrafish and mice have demonstrated that Gpr126 plays an essential role in neural, cardiac and ear development. In addition, genome-wide association studies have implicated variations at the GPR126 locus in obstructive pulmonary dysfunction, in scoliosis and as a determinant of trunk length and body height. Gpr126 appears to exert its function depending on the organ system via G protein- and/or N-terminus-dependent signaling. Here, we review the current knowledge about Gpr126, which, due to the variety of its functions and its multiple signaling modalities, provides a model adhesion GPCR to understand general functional concepts utilized by adhesion GPCRs

The multiple signaling modalities of adhesion G protein-coupled receptor GPR126 in development

The G protein-coupled receptor (GPCR) superfamily is the largest known receptor family in the human genome. Although the family of adhesion GPCRs comprises the second largest sub-family, their function is poorly understood. Here, we review the current knowledge about the adhesion GPCR family member GPR126. GPR126 possesses a signal peptide, a 7TM domain homologous to secretin-like GPCRs, a GPS motif and an extended N-terminus containing a CUB (Complement, Uegf, Bmp1) domain, a PTX (Pentraxin) domain, a hormone binding domain and 27 putative N-glycosylation sites. Knockdown and knockout experiments in zebrafish and mice have demonstrated that Gpr126 plays an essential role in neural, cardiac and ear development. In addition, genome-wide association studies have implicated variations at the GPR126 locus in obstructive pulmonary dysfunction, in scoliosis and as a determinant of trunk length and body height. Gpr126 appears to exert its function depending on the organ system via G-protein- and/or N-terminus-dependent signaling. Here, we review the current knowledge about Gpr126, which, due to the variety of its functions and its multiple signaling modalities, provides a model adhesion GPCR to understand general functional concepts utilized by adhesion GPCRs

Adhesion GPCRs in Kidney Development and Disease

Chronic kidney disease (CKD) represents the fastest growing pathology worldwide with a prevalence of >10% in many countries. In addition, kidney cancer represents 5% of all new diagnosed cancers. As currently no effective therapies exist to restore kidney function after CKD- as well as cancer-induced renal damage, it is important to elucidate new regulators of kidney development and disease as new therapeutic targets. G protein-coupled receptors (GPCRs) represent the most successful class of pharmaceutical targets. In recent years adhesion GPCRs (aGPCRs), the second largest GPCR family, gained significant attention as they are present on almost all mammalian cells, are associated to a plethora of diseases and regulate important cellular processes. aGPCRs regulate for example cell polarity, mitotic spindle orientation, cell migration, and cell aggregation; all processes that play important roles in kidney development and/or disease. Moreover, polycystin-1, a major regulator of kidney development and disease, contains a GAIN domain, which is otherwise only found in aGPCRs. In this review, we assess the potential of aGPCRs as therapeutic targets for kidney disease. For this purpose we have summarized the available literature and analyzed data from the databases The Human Protein Atlas, EURExpress, Nephroseq, FireBrowse, cBioPortal for Cancer Genomics and the National Cancer Institute Genomic Data Commons data portal (NCIGDC). Our data indicate that most aGPCRs are expressed in different spatio-temporal patterns during kidney development and that altered aGPCR expression is associated with a variety of kidney diseases including CKD, diabetic nephropathy, lupus nephritis as well as renal cell carcinoma. We conclude that aGPCRs present a promising new class of therapeutic targets and/or might be useful as diagnostic markers in kidney disease

The Threat of Capital Drain: A Rationale for Public Banks?

This paper yields a rationale for why subsidized public banks may be desirable from a regional perspective in a financially integrated economy. We present a model with credit rationing and heterogeneous regions in which public banks prevent a capital drain from poorer to richer regions by subsidizing local depositors, for example, through a public guarantee. Under some conditions, cooperative banks can perform the same function without any subsidization; however, they may be crowded out by public banks. We also discuss the impact of the political structure on the emergence of public banks in a political-economy setting and the role of interregional mobility

TWEAK-Fn14 cytokine-receptor axis: a new player of myocardial remodeling and cardiac failure

Tumor necrosis factor (TNF) has been firmly established as a pathogenic factor in heart failure, a significant socio-economic burden. In this review, we will explore the role of other members of the TNF/TNF receptor superfamily (TNFSF/TNFRSF) in cardiovascular diseases (CVDs) focusing on TWEAK and its receptor Fn14, new players in myocardial remodeling and heart failure. The TWEAK/Fn14 pathway controls a variety of cellular activities such as proliferation, differentiation, and apoptosis and has diverse biological functions in pathological mechanisms like inflammation and fibrosis that are associated with CVDs. Furthermore, it has recently been shown that the TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy and that deletion of Fn14 receptor protects from right heart fibrosis and dysfunction. We discuss the potential use of the TWEAK/Fn14 axis as biomarker for CVDs as well as therapeutic target for future treatment of human heart failure based on supporting data from animal models and in vitro studies. Collectively, existing data strongly suggest the TWEAK/Fn14 axis as a potential new therapeutic target for achieving cardiac protection in patients with CVDs

Gpr126 functions in schwann cells to control differentiation and myelination via G-protein activation

The myelin sheath surrounding axons ensures that nerve impulses travel quickly and efficiently, allowing for the proper function of the vertebrate nervous system. We previously showed that the adhesion G-protein-coupled receptor (aGPCR) Gpr126 is essential for peripheral nervous system myelination, although the molecular mechanisms by which Gpr126 functions were incompletely understood. aGPCRs are a significantly understudied protein class, and it was unknown whether Gpr126 couples to G-proteins. Here, we analyze Dhh(Cre);Gpr126(fl/fl) conditional mutants, and show that Gpr126 functions in Schwann cells (SCs) for radial sorting of axons and myelination. Furthermore, we demonstrate that elevation of cAMP levels or protein kinase A activation suppresses myelin defects in Gpr126 mouse mutants and that cAMP levels are reduced in conditional Gpr126 mutant peripheral nerve. Finally, we show that GPR126 directly increases cAMP by coupling to heterotrimeric G-proteins. Together, these data support a model in which Gpr126 functions in SCs for proper development and myelination and provide evidence that these functions are mediated via G-protein-signaling pathways

Inferring cell cycle feedback regulation from gene expression data

AbstractFeedback control is an important regulatory process in biological systems, which confers robustness against external and internal disturbances. Genes involved in feedback structures are therefore likely to have a major role in regulating cellular processes.Here we rely on a dynamic Bayesian network approach to identify feedback loops in cell cycle regulation. We analyzed the transcriptional profile of the cell cycle in HeLa cancer cells and identified a feedback loop structure composed of 10 genes. In silico analyses showed that these genes hold important roles in system’s dynamics. The results of published experimental assays confirmed the central role of 8 of the identified feedback loop genes in cell cycle regulation.In conclusion, we provide a novel approach to identify critical genes for the dynamics of biological processes. This may lead to the identification of therapeutic targets in diseases that involve perturbations of these dynamics

Transcriptional Profiling of Caudal Fin Regeneration in Zebrafish

Regeneration of severed limbs in adult animals is restricted to urodele amphibians. Mammals, including humans, have very limited regenerative capabilities and even with proper treatment, only the tips of our digits can grow back. Teleost fish can regenerate amputated fins, the evolutionary ancestors of limbs. To elucidate the principles of limb-fin regeneration, we performed an Affymetrix microarray screen on regenerating caudal fins 12, 24, 48, and 72 h post amputation. Approximately 15,000 zebrafish transcripts were analyzed, identifying 829 transcripts as differentially expressed during regeneration. Of those, 563 were up-regulated and 266 were down-regulated. We constructed a comprehensive database containing expression data, functional assignment, and background information from the literature for each differentially expressed transcript. In order to validate our findings, we employed three approaches: (1) microarray expression analysis of genes previously implicated in fin regeneration, (2) RT-PCR analysis of genes newly identified as differentially expressed during regeneration, and (3) in situ hybridization of the up-regulated genes bambi, dlx5A, and her6. Moreover, we show that Smad 1/5/8 proteins, effector molecules of Bmp signaling, are phosphorylated during fin regeneration. Taken together, we provide a comprehensive database of fin regeneration that will serve as an important tool for understanding the molecular mechanisms of regeneration

Recombinant spider silk protein eADF4(C16)-RGD coatings are suitable for cardiac tissue engineering

Cardiac tissue engineering is a promising approach to treat cardiovascular diseases, which are a major socio-economic burden worldwide. An optimal material for cardiac tissue engineering, allowing cardiomyocyte attachment and exhibiting proper immunocompatibility, biocompatibility and mechanical characteristics, has not yet emerged. An additional challenge is to develop a fabrication method that enables the generation of proper hierarchical structures and constructs with a high density of cardiomyocytes for optimal contractility. Thus, there is a focus on identifying suitable materials for cardiac tissue engineering. Here, we investigated the interaction of neonatal rat heart cells with engineered spider silk protein (eADF4(C16)) tagged with the tripeptide arginyl-glycyl-aspartic acid cell adhesion motif RGD, which can be used as coating, but can also be 3D printed. Cardiomyocytes, fibroblasts, and endothelial cells attached well to eADF4(C16)-RGD coatings, which did not induce hypertrophy in cardiomyocytes, but allowed response to hypertrophic as well as proliferative stimuli. Furthermore, Kymograph and MUSCLEMOTION analyses showed proper cardiomyocyte beating characteristics on spider silk coatings, and cardiomyocytes formed compact cell aggregates, exhibiting markedly higher speed of contraction than cardiomyocyte mono-layers on fibronectin. The results suggest that eADF4(C16)-RGD is a promising material for cardiac tissue engineering

Myogenin controls via AKAP6 non-centrosomal microtubule-organizing center formation at the nuclear envelope

Non-centrosomal microtubule-organizing centers (MTOCs) are pivotal for the function of multiple cell types, but the processes initiating their formation are unknown. Here, we find that the transcription factor myogenin is required in murine myoblasts for the localization of MTOC proteins to the nuclear envelope. Moreover, myogenin is sufficient in fibroblasts for nuclear envelope MTOC (NE-MTOC) formation and centrosome attenuation. Bioinformatics combined with loss- and gain-of-function experiments identified induction of AKAP6 expression as one central mechanism for myogenin-mediated NE-MTOC formation. Promoter studies indicate that myogenin preferentially induces the transcription of muscle- and NE-MTOC-specific isoforms of Akap6 and Syne1, which encodes nesprin-1α, the NE-MTOC anchor protein in muscle cells. Overexpression of AKAP6β and nesprin-1α was sufficient to recruit endogenous MTOC proteins to the nuclear envelope of myoblasts in the absence of myogenin. Taken together, our results illuminate how mammals transcriptionally control the switch from a centrosomal MTOC to an NE-MTOC and identify AKAP6 as a novel NE-MTOC component in muscle cells