Regulation Of Organ Development Research Articles

Gene Expression Profiles Controlled by the Alternative Splicing Factor Nova2 in Endothelial Cells.

Alternative splicing (AS) plays an important role in expanding the complexity of the human genome through the production of specialized proteins regulating organ development and physiological functions, as well as contributing to several pathological conditions. How AS programs impact on the signaling pathways controlling endothelial cell (EC) functions and vascular development is largely unknown. Here we identified, through RNA-seq, changes in mRNA steady-state levels in ECs caused by the neuro-oncological ventral antigen 2 (Nova2), a key AS regulator of the vascular morphogenesis. Bioinformatics analyses identified significant enrichment for genes regulated by peroxisome proliferator-activated receptor-gamma (Ppar-γ) and E2F1 transcription factors. We also showed that Nova2 in ECs controlled the AS profiles of Ppar-γ and E2F dimerization partner 2 (Tfdp2), thus generating different protein isoforms with distinct function (Ppar-γ) or subcellular localization (Tfdp2). Collectively, our results supported a mechanism whereby Nova2 integrated splicing decisions in order to regulate Ppar-γ and E2F1 activities. Our data added a layer to the sequential series of events controlled by Nova2 in ECs to orchestrate vascular biology.

Abstract P2003: Loss of Trpa1 in Mice Leads to Age-Related Dilated Cardiomyopathy

Activation of the transient receptor potential ankyrin 1 (TRPA1) channel, a mechanical and oxidative stress sensor, has been shown to slow down aging process and promote longevity in invertebrate animal models like Caenorhabditis elegans . Although physiologic sensory functions of TRPA1 are conservative across species, the role of TRPA1 in regulation of organ development and function in mammals in the aging process is unknown. The present study tests the hypothesis that TRPA1 ablation leads to cardiac dilation and cardiomyopathy in aging mice. Echocardiography was performed in male 12-week-old (young) and 52-week-old (older) Trpa1 gene knockout ( Trpa1 -/- ) mice and wild-type (WT) littermates on a mixed C57BL/6 x 129 genetic background. Echocardiogram data showed that, compared to young WT littermates, young Trpa1 -/- mice had similar cardiac dimensions and left ventricular function, as demonstrated by left ventricular end-diastolic internal dimension (LVIDd, WT 4.29±0.62 vs. Trpa1 -/- 4.50±0.41 mm, P>0.05), left ventricular ejection fraction (LVEF, a parameter of systolic function, WT 66.73±9.50 vs. Trpa1 -/- 63.39±12.76 %, P>0.05), and E/A ratio (a parameter of diastolic function, WT 1.23±0.03 vs. Trpa1 -/- 1.39±0.14, P>0.05). In contrast, older Trpa1 -/- mice developed dilated cardiomyopathy with dilated left ventricle (LVIDd: WT 4.60±0.16 vs. Trpa1 -/- 5.00±0.37 mm, P<0.05) and impaired left ventricular systolic function (LVEF: WT 58.04±9.27 vs. Trpa1 -/- 41.79±7.19 %, P<0.05) when compared to older WT mice. In addition, older Trpa1 -/- mice had impaired left ventricular myocardial performance index (LV MPI, a parameter of ventricular systolic and diastolic function, WT 0.62±0.15 vs. Trpa1 -/- 0.89±0.18, P<0.05) albeit left ventricular diastolic function was not different between old Trpa1 -/- and WT mice (E/A ratio: WT 1.53±0.22 vs. Trpa1 -/- 1.99±0.92, P>0.05). These results show that genetic knockout of TRPA1 leads to age-related left ventricular dilation and systolic dysfunction. These findings suggest that TRPA1 activation protects against age-related dilated cardiomyopathy.

Abstract 3086: Discovery of a first-in-class TEAD inhibitor which directly inhibits YAP/TAZ-TEAD protein-protein interaction and shows a potent anti-tumor effect in malignant pleural mesothelioma

Abstract Objective: Hippo signaling pathway is known to regulate organ development. In Hippo signaling pathway, YAP or TAZ works as a transcriptional co-activator and forms a transcriptional complex with TEAD. In several cancers, upstream factors in Hippo pathway are inactivated by genetic alterations. When the upstream factors are inactivated, TEAD is activated and forms a complex with YAP/TAZ resulting in enhancement of cell proliferation, drug resistance and so on. In the activation process, S-palmitoylation of TEAD is necessary for binding to YAP/TAZ. Malignant pleural mesothelioma (MPM) is one of cancer types which have genetic alterations in Hippo pathway genes. Although YAP/TAZ-TEAD inhibitor should be an ideal drug for MPM therapy, there are only a few reports about YAP/TAZ-TEAD inhibitor and the efficacy and selectivity are not sufficient. In this study, we succeeded to synthesize a small molecule TEAD inhibitor, K-975, and evaluated its mechanism of action and anti-tumor effect against MPM. Materials/methods: Inhibitory activity of K-975 on YAP/TAZ-TEAD protein-protein interaction (PPI) was evaluated in surface plasmon resonance (SPR) and co-immunoprecipitation assay. The effect of K-975 on palmitoylation status of TEAD was also evaluated. The three-dimensional structure of YAP-binding domain of TEAD1 in complex with K-975 was determined by X-ray crystallography. Anti-tumor effect of K-975 was evaluated by using MPM cell lines. Furthermore, using a derivative of K-975, 2 week-toxicity studies in rats and monkeys were performed. Results: K-975 inhibited YAP-TEAD and TAZ-TEAD PPI in NCI-H226 cells, a human MPM cell line. Also, K-975 inhibited palmitoylation of TEAD. The crystal structure revealed that K-975 directly bound to cysteine residue in YAP-binding domain of TEAD1. This cysteine residue is highly conserved in TEAD family and known as a site of S-palmitoylation. K-975 inhibited the cell proliferation of NCI-H226 with GI50 of about 20 nmol/L. K-975 also induced a change of gene expressions similar to that induced by YAP knockdown. In vivo experiments, K-975 strongly suppressed the tumor growth in several s.c. xenograft models and showed a significant survival benefit in an orthotopic xenograft model. However, 2 week-toxicity studies of a K-975 derivative with optimized bioavailability showed some pathological findings which suggested the renal toxicity. Conclusion: We synthesized a first-in-class drug which directly binds to TEAD protein and inhibits YAP/TAZ-TEAD PPI. K-975 showed a strong anti-tumor effect in pre-clinical MPM models. Although the renal toxicity might cause some difficulty in clinical use, we believe that a K-975 derivative has a possibility to become an effective drug candidate for MPM therapy. Citation Format: Ayumi Kaneda, Toshihiro Seike, Takeshi Uemori, Kensuke Myojo, Kensuke Aida, Tomohiro Danjo, Takahiro Nakajima, Daisuke Yamaguchi, Tomoko Hamada, Yoshiro Tsuji, Kaori Hamaguchi, Mai Yasunaga, Nobumasa Otsubo, Hideyuki Onodera, Yoichi Nishiya, Michihiko Suzuki, Junichi Saito, Toshihiko Ishii, Ryuichiro Nakai. Discovery of a first-in-class TEAD inhibitor which directly inhibits YAP/TAZ-TEAD protein-protein interaction and shows a potent anti-tumor effect in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3086.

Alternative splicing of the clathrin heavy chain impacts skeletal muscle physiology and protects hearts from failure

Alternative splicing is a posttranscriptional mechanism that produces multiple protein isoforms from a single gene. More than 90% of human genes undergo alternative splicing1,2. Coordinated splicing networks regulate organ development and tissue identity3 and genes encoding trafficking proteins are highly regulated by alternative splicing4. In particular, alternative splicing of the clathrin heavy chain (Cltc) gene regulates the expression of specific splice variants during striated muscle development5,6. CLTC is the main driver of clathrin mediated endocytosis; but also regulates the formation and maintenance of the costamere in skeletal muscles7. Nothing is known about the physiological impact of CLTC splicing, leading us to hypothesize that splicing regulation of CLTC contributes to heart and skeletal muscle physiology. We are using our new CRISPR mouse model where the endogenous Cltc splicing transition is blocked: homozygous Cltc‐ho mice express exclusively the fetal isoform throughout development while in wild type Cltc‐wt mice normal Cltc splicing transition takes place8.We first characterized Cltc splicing patterns of in wild type animals during development in different tissues and demonstrated that exon 31 is skipped in neonates but included in adulthood exclusively in the heart, skeletal muscles, and brain. We observed the developmental regulation in human samples. Furthermore, splicing of Cltc gene reverted to neonatal patterns in mouse hearts after aortic constriction (TAC), a well‐established model of heart failure. Physiologically, Cltc‐ho mice exhibited a higher body and skeletal muscle weights than Cltc‐wt littermates that is accompanied by the downregulation of myostatin expression and the AMPK‐signaling pathway. Notably, hearts are similar in basal conditions; however, when TAC surgeries were performed in these animals, Cltc‐wt mice developed heart failure and hypertrophy whereas Cltc‐ho littermates were protected from cardiac dysfunction. Our ongoing experiments are investigating the different signaling pathways that control the observed phenotypes. Alternative splicing and membrane trafficking are fundamental cellular processes; however, we do not know how splicingtrafficking networks modulate tissue identity acquisition and maintenance, or cellular architecture. Therefore, the interaction between alternative splicing and trafficking is the knowledge gap inspiring our present and future work.Support or Funding InformationStart‐up funds, Junior Faculty Development Award, Nutrition Obesity Research Center (NORC) Pilot and Feasibility Grant (P30DK056350) from The University of North Carolina at Chapel Hill (to JG).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

BIGGER ORGANS and ELEPHANT EAR-LIKE LEAF1 control organ size and floral organ internal asymmetry in pea.

Control of organ size and shape by cell proliferation and cell expansion is a fundamental process during plant development, but the molecular mechanisms that set the final size and shape of determinate organs in plants remain unclear, especially in legumes. In this study, we characterized several mutants including bigger organs (bio) and elephant-ear-like leaf 1 (ele1) in pea that displayed similar phenotypes, with enlarged leaves and symmetrical lateral and ventral petals. Genetic analysis showed that BIO interacted with the specific regulators SYMMETRICAL PETAL1 (SYP1) and SYP5 to control floral organ internal asymmetry in pea. Using a comparative approach, we cloned BIO and ELE1, revealing that they encode a KIX domain protein and an ortholog of Arabidopsis PEAPOD (PPD), respectively. Furthermore, genetic analysis, physical interaction assays, and gene expression analysis showed that BIO and ELE1 physically interact with each other and with the transcription factor LATHYROIDES (LATH) to repress expression of downstream genes such as GROWTH-REGULATING-FACTOR 5. Our data show that the BIO-ELE1 module in legumes plays a key role in regulating organ development to create distinct final forms with characteristic size and shape.

Characterization of a Genomic Region under Selection in Cultivated Carrot (Daucus carota subsp. sativus) Reveals a Candidate Domestication Gene.

Carrot is one of the most important vegetables worldwide, owing to its capability to develop fleshy, highly nutritious storage roots. It was domesticated ca. 1,100 years ago in Central Asia. No systematic knowledge about the molecular mechanisms involved in the domestication syndrome in carrot are available, however, the ability to form a storage root is undoubtedly the essential transition from the wild Daucus carota to the cultivated carrot. Here, we expand on the results of a previous study which identified a polymorphism showing a significant signature for selection upon domestication. We mapped the region under selection to the distal portion of the long arm of carrot chromosome 2, confirmed that it had been selected, as reflected in both the lower nucleotide diversity in the cultivated gene pool, as compared to the wild (πw/πc = 7.4 vs. 1.06 for the whole genome), and the high FST (0.52 vs. 0.12 for the whole genome). We delimited the region to ca. 37 kb in length and identified a candidate domestication syndrome gene carrying three non-synonymous single nucleotide polymorphisms and one indel systematically differentiating the wild and the cultivated accessions. This gene, DcAHLc1, belongs to the AT-hook motif nuclear localized (AHL) family of plant regulatory genes which are involved in the regulation of organ development, including root tissue patterning. AHL genes work through direct interactions with other AHL family proteins and a range of other proteins that require intercellular protein movement. Based on QTL data on root thickening we speculate that DcAHLc1 might be involved in the development of the carrot storage root, as the localization of the gene overlapped with one of the QTLs. According to haplotype information we propose that the ‘cultivated’ variant of DcAHLc1 has been selected from wild Central Asian carrot populations upon domestication and it is highly predominant in the western cultivated carrot gene pool. However, some primitive eastern landraces and the derived B7262 purple inbred line still carry the ‘wild’ variant, reflecting a likely complexity of the genetic determination of the formation of carrot storage roots.

Decipher the ancestry of the plant-specific LBD gene family

BackgroundLateral Organ Boundaries Domain (LBD) genes arise from charophyte algae and evolve essential functions in land plants in regulating organ development and secondary metabolism. Although diverse plant species have been investigated to construct the phylogeny of LBD gene family, a detailed and reliable ancestry that characterizes their evolutionary patterns has not been revealed.ResultsWe develop an improved bioinformatic method that allows robust detection of 431 LBD genes in 11 high-quality land plant genomes. Phylogenetic analysis classifies the LBD genes into six subfamilies which support the existence of 7 ancient gene lineages. Phylogenetic relationship and gene collinearity are combined to retrace 11 ancestor genes for seed plants and 18 ancestor genes for angiosperms, which improves the resolution of LBD gene ancestry. The ancient gene lineages are strictly preserved in current plant genomes, including the previously controversial class IB gene in Selaginella moellendorphii, suggesting extreme reluctance of LBD genes to be lost during evolution. Meanwhile, whole-genome and dispersed gene duplications substantially expand LBD gene family in angiosperms, and elaborate functions of LBD genes through frequent expression pattern change and protein sequence variation.ConclusionsThrough phylogenetic and gene collinearity analyses, we retrace the landscape of LBD gene ancestry which lays foundation for elucidating evolutionary diversification of LBD genes in land plants.

Selenoprotein H is an essential regulator of redox homeostasis that cooperates with p53 in development and tumorigenesis

Selenium, an essential micronutrient known for its cancer prevention properties, is incorporated into a class of selenocysteine-containing proteins (selenoproteins). Selenoprotein H (SepH) is a recently identified nucleolar oxidoreductase whose function is not well understood. Here we report that seph is an essential gene regulating organ development in zebrafish. Metabolite profiling by targeted LC-MS/MS demonstrated that SepH deficiency impairs redox balance by reducing the levels of ascorbate and methionine, while increasing methionine sulfoxide. Transcriptome analysis revealed that SepH deficiency induces an inflammatory response and activates the p53 pathway. Consequently, loss of seph renders larvae susceptible to oxidative stress and DNA damage. Finally, we demonstrate that seph interacts with p53 deficiency in adulthood to accelerate gastrointestinal tumor development. Overall, our findings establish that seph regulates redox homeostasis and suppresses DNA damage. We hypothesize that SepH deficiency may contribute to the increased cancer risk observed in cohorts with low selenium levels.

Structure–activity studies of Wnt/β-catenin inhibition in the Niclosamide chemotype: Identification of derivatives with improved drug exposure

The Wnt signaling pathway plays a key role in regulation of organ development and tissue homeostasis. Dysregulated Wnt activity is one of the major underlying mechanisms responsible for many diseases including cancer. We previously reported the FDA-approved anthelmintic drug Niclosamide inhibits Wnt/β-catenin signaling and suppresses colon cancer cell growth in vitro and in vivo. Niclosamide is a multi-functional drug that possesses important biological activity in addition to inhibition of Wnt/β-catenin signaling. Here, we studied the SAR of Wnt signaling inhibition in the anilide and salicylamide region of Niclosamide. We found that the 4′-nitro substituent can be effectively replaced by trifluoromethyl or chlorine and that the potency of inhibition was dependent on the substitution pattern in the anilide ring. Non-anilide, N-methyl amides and reverse amide derivatives lost significant potency, while acylated salicylamide derivatives inhibited signaling with potency similar to non-acyl derivatives. Niclosamide’s low systemic exposure when dosed orally may hinder its use to treat systemic disease. To overcome this limitation we identified an acyl derivative of Niclosamide, DK-520 (compound 32), that significantly increased both the plasma concentration and the duration of exposure of Niclosamide when dosed orally. The studies herein provide a medicinal chemical foundation to improve the pharmacokinetic exposure of Niclosamide and Wnt-signaling inhibitors based on the Niclosamide chemotype. The identification of novel derivatives of Niclosamide that metabolize to Niclosamide and increase its drug exposure may provide important research tools for in vivo studies and provide drug candidates for treating cancers with dysregulated Wnt signaling including drug-resistant cancers. Moreover, since Niclosamide is a multi-functional drug, new research tools such as DK520 could directly result in novel treatments against bacterial and viral infection, lupus, and metabolic diseases such as type II diabetes, NASH and NAFLD.

Regulation of lung development and regeneration by the vascular system.

Blood vessels have been described a long time ago as passive circuits providing sufficient blood supply to ensure proper distribution of oxygen and nutrition. Blood vessels are mainly formed during embryonic development and in the early postnatal period. In the adult, blood vessels are quiescent, but can be activated and subsequently induced under pathophysiological conditions, such as ischemia and tumor growth. Surprisingly, recent data have suggested an active function for blood vessels, named angiocrine signaling, releasing trophogens which regulate organ development and organ regeneration including in the pancreas, lung, tumor cells, liver and bone. Lung development is driven by hypoxia as well as an intense endothelial-epithelial interaction, and important mechanisms contributing to these processes have recently been identified. This review aims to summarize recent developments and concepts about embryonic pulmonary vascular development and lung regeneration. We discuss hypoxia-inducible factor HIF-2α and vascular endothelial growth factor VEGF as important mediators in lung development and focus on endothelial-epithelial interactions and angiocrine signaling mechanisms.

Mobility of signaling molecules: the key to deciphering plant organogenesis.

Signaling molecules move between cells to form a characteristic distribution pattern within a developing organ; thereafter, they spatiotemporally regulate organ development. A key question in this process is how the signaling molecules robustly form the precise distribution on a tissue scale in a reproducible manner. Despite of an increasing number of quantitative studies regarding the mobility of signaling molecules, the detail mechanism of organogenesis via intercellular signaling is still unclear. We here review the potential advantages of plant development to address this question, focusing on the cytoplasmic continuity of plant cells through the plasmodesmata. The plant system would provide a unique opportunity to define the simple transportation mode of diffusion process, and, hence, the mechanism of organogenesis via intercellular signaling. Based on the advances in the understanding of intercellular signaling at the molecular level and in the quantitative imaging techniques, we discuss our current challenges in measuring the mobility of signaling molecules for deciphering plant organogenesis.

Differentiated expression of microRNAs may regulate genotype-dependent traits in cotton.

miRNA is an exogenous non-coding RNA with 21-24nt in length, which plays a crucial role in almost all biological processes. In plants, miRNAs regulate organ development, phase change, signal transduction and response to different biotic and abiotic stresses at the post-transcriptional levels. Although there are many studies on plant miRNAs, no studies have been focused on the genotype dependence. Genotype-dependent traits may be controlled by the differential expression of certain miRNAs. To test this hypothesis, we investigated the expression profile patterns of 11 selected miRNAs in 5 different organs in 5 different cotton cultivars and their implication on plant development. Our results demonstrate that miRNAs have different expression patterns in different plant organs in different genotypes, which implicate their different traits, including early flowering. miR172 is a miRNA controlling floral development and phase change; our results show that miR172 has a higher expression level in the flower bud than in any other organ, our results also show that Baimian cultivars have a higher expression of miR172 than TM-1. This suggests that Baimian cultivars have an earlier transition from vegetable growth to reproductive growth, which is confirmed by our development data on floral branch development. Our result also shows that several miRNAs, including miR159 and miR162, were highly expressed in Baimian cultivars. The results obtained in this study would provide new insight for improving cotton using miRNA-based biotechnology.

Genome-wide identification and characterization of miRNAs in the hypocotyl and cotyledon of cauliflower (Brassica oleracea L. var. botrytis) seedlings

MicroRNAs (miRNAs) are a class of small endogenous, non-coding RNAs that have key regulatory functions in plant growth, development, and other biological processes. Hypocotyl and cotyledon are the two major tissues of cauliflower (Brassica oleracea L. var. botrytis) seedlings. Tissue culture experiments have indicated that the regenerative abilities of these two tissues are significantly different. However, the characterization of miRNAs and their roles in regulating organ development in cauliflower remain unexplored. In the present study, two small RNA libraries were sequenced by Solexa sequencing technology. 99 known miRNAs belonging to 28 miRNA families were identified, in which 6 miRNA families were detected only in Brassicaceae. A total of 162 new miRNA sequences with single nucleotide substitutions corresponding to the known miRNAs, and 32 potentially novel miRNAs were also first discovered. Comparative analysis indicated that 42 of 99 known miRNAs and 17 of 32 novel miRNAs exhibited significantly differential expression between hypocotyl and cotyledon, and the differential expression of several miRNAs was further validated by stem-loop RT-PCR. In addition, 235 targets for 89 known miRNAs and 198 targets for 24 novel miRNAs were predicted, and their functions were further discussed. The expression patterns of several representative targets were also confirmed by qRT-PCR analysis. The results identified that the transcriptional expression patterns of miRNAs were negatively correlated with their targets. These findings gave new insights into the characteristics of miRNAs in cauliflower, and provided important clues to elucidate the roles of miRNAs in the tissue differentiation and development of cauliflower.

Genome-Wide Identification of KANADI1 Target Genes

Plant organ development and polarity establishment is mediated by the action of several transcription factors. Among these, the KANADI (KAN) subclade of the GARP protein family plays important roles in polarity-associated processes during embryo, shoot and root patterning. In this study, we have identified a set of potential direct target genes of KAN1 through a combination of chromatin immunoprecipitation/DNA sequencing (ChIP-Seq) and genome-wide transcriptional profiling using tiling arrays. Target genes are over-represented for genes involved in the regulation of organ development as well as in the response to auxin. KAN1 affects directly the expression of several genes previously shown to be important in the establishment of polarity during lateral organ and vascular tissue development. We also show that KAN1 controls through its target genes auxin effects on organ development at different levels: transport and its regulation, and signaling. In addition, KAN1 regulates genes involved in the response to abscisic acid, jasmonic acid, brassinosteroids, ethylene, cytokinins and gibberellins. The role of KAN1 in organ polarity is antagonized by HD-ZIPIII transcription factors, including REVOLUTA (REV). A comparison of their target genes reveals that the REV/KAN1 module acts in organ patterning through opposite regulation of shared targets. Evidence of mutual repression between closely related family members is also shown.

Reconstituting pancreas development from purified progenitor cells reveals genes essential for islet differentiation

Developmental biology is challenged to reveal the function of numerous candidate genes implicated by recent genome-scale studies as regulators of organ development and diseases. Recapitulating organogenesis from purified progenitor cells that can be genetically manipulated would provide powerful opportunities to dissect such gene functions. Here we describe systems for reconstructing pancreas development, including islet β-cell and α-cell differentiation, from single fetal progenitor cells. A strict requirement for native genetic regulators of in vivo pancreas development, such as Ngn3, Arx, and Pax4, revealed the authenticity of differentiation programs in vitro. Efficient genetic screens permitted by this system revealed that Prdm16 is required for pancreatic islet development in vivo. Discovering the function of genes regulating pancreas development with our system should enrich strategies for regenerating islets for treating diabetes mellitus.

Numerical Analysis of Steady State Patterns in Cell-Based Auxin Transport Models

Cell-based models that describe the pattern formation and the flow of chemicals in plant organs are important building blocks in a multiscale simulation of a whole plant. An example of an important mechanism is the transport of the hormone auxin throughout the plant's organs because it is closely related to the growth characteristics of roots, shoots and leaves. Based on experimental evidence, a number of cell-based auxin transport models were developed. Due to the intercellular transport of chemicals, these models are complex dynamical systems with a large set of endogenous and exogenous parameters. The models share underlying mathematicalprinciples w.r.t. steady state pattern formation which plays a central role in the growth and development of plant organs. This calls for a uniform computational approach. In our research we focus on computer simulations of general cell-based transport models and more specically we use numerical bifurcation analysis to study the steady state patterns. It indicates how the stability ofpatterns is lost or gained as the system parameters change. Bifurcation analysis of ODEs is widespread in biology and various numerical tools produce bifurcation diagrams. However, these automatic tools do not work for large scale problems, such as biological patterning. Indeed, realistic simulations of large tissues that take multiple interacting chemicals into account give rise to very large and sparse systems of coupled ODEs. We analyze recent large scale transport models with new mathematical and computational tools that enable quantitative prediction of the bifurcations that appear at the macroscopic level in these models. This allows us to predict the patterns and self-similar solutions that appear during organ growth and to see how their stability changes as endogenous parameters are modified or as externally applied changes are enforced. We use these methods to compare the model output with observed data such as the auxin distribution and venation patterns in leaves in order to get a better understanding of the processes that regulate organ development in plants.

Generation and characterization of KsprtTA and KsptTA transgenic mice

The advent of technologies that allow tissue specific expression or ablation of genes has contributed enormously to our knowledge of the mechanism regulating organ development and maintenance in mice. The tetracycline inducible system allows reversible regulation of gene products upon administration of doxycycline. Here we describe the generation and activity of two transgenic lines expressing the cDNAs for the Tet responsive transcription factors rtTA and tTA (Tet-on and off) respectively under the control of an element that drives expression in the epithelium of the developing and adult kidney. Both lines show inducible and reversible activity in the embryonic and adult organ.

Midkine in Inflammatory and Toxic Conditions

Midkine (MK) is a member of midkine family which is composed of MK and pleotrophin (PTN). MK behaves like a cytokine and growth factor, promotes the proliferation, differentiation, survival, adhesion, migration of cells. MK expression usually increases during ischemia, inflammation, tissue repair, neoplastic transformation and in different toxic conditions. Immune cells and most of organs have MK secretion function in fetal and adult life. MK could be a promising prognostic/diagnostic marker and a potential target in many of diseases including malignancy, toxic and inflammatory diseases. This review focuses on both cell protective and immune-modulatory roles of MK in different in vitro and in vivo disease models and human reports. MK is still a novel molecule in the regulation of organ development and the etiology of many diseases.

Of Timescales, Animal Models, and Human Disease: The 50th Anniversary of C. elegans as a Biological Model

Of Timescales, Animal Models, and Human Disease: The 50th Anniversary of C. elegans as a Biological Model

Morphogen Pathways in Systemic Sclerosis

The morphogen pathways Wnt, hedgehog, and Notch are key regulators of organ development and tissue homeostasis. In adults, the tightly regulated activity of morphogen pathways is essential for cell renewal and tissue regeneration. Loss of control and persistent activation of morphogen pathways, however, can lead to a variety of diseases, including malignancy and fibrotic disorders. In recent years, pathological activation of Wnt, hedgehog, and Notch pathways have been described in systemic sclerosis (SSc) and other fibrotic diseases. Experimental models reveal that morphogen pathways drive fibroblast activation and collagen release. In these model systems, genetic or pharmacological blockade of morphogen pathways inhibits collagen release and reduces experimental fibrosis. Importantly, inhibitors for Wnt, hedgehog, and Notch are already in clinical evaluation, thereby emphasizing the translational implications of these findings. Further experimental studies, however, should deepen our knowledge before initiating clinical trials with inhibitors of morphogen pathways.