Foxf2: A Novel Locus for Anterior Segment Dysgenesis Adjacent to the Foxc1 Gene

Anterior segment dysgenesis (ASD) is characterised by an abnormal migration of neural crest cells or an aberrant differentiation of the mesenchymal cells during the formation of the eye's anterior segment. These abnormalities result in multiple tissue defects affecting the iris, cornea and drainage structures of the iridocorneal angle including the ciliary body, trabecular meshwork and Schlemm's canal. In some cases, abnormal ASD development leads to glaucoma, which is usually associated with increased intraocular pressure. Haploinsufficiency through mutation or chromosomal deletion of the human FOXC1 transcription factor gene or duplications of the 6p25 region is associated with a spectrum of ocular abnormalities including ASD. However, mapping data and phenotype analysis of human deletions suggests that an additional locus for this condition may be present in the same chromosomal region as FOXC1. DHPLC screening of ENU mutagenised mouse archival tissue revealed five novel mouse Foxf2 mutations. Re-derivation of one of these (the Foxf2W174R mouse lineage) resulted in heterozygote mice that exhibited thinning of the iris stroma, hyperplasia of the trabecular meshwork, small or absent Schlemm's canal and a reduction in the iridocorneal angle. Homozygous E18.5 mice showed absence of ciliary body projections, demonstrating a critical role for Foxf2 in the developing eye. These data provide evidence that the Foxf2 gene, separated from Foxc1 by less than 70 kb of genomic sequence (250 kb in human DNA), may explain human abnormalities in some cases of ASD where FOXC1 has been excluded genetically

The Tumor Suppressor PRDM5 Regulates Wnt Signaling at Early Stages of Zebrafish Development

PRDM genes are a family of transcriptional regulators that modulate cellular processes such as differentiation, cell growth and apoptosis. Some family members are involved in tissue or organ maturation, and are differentially expressed in specific phases of embryonic development. PRDM5 is a recently identified family member that functions as a transcriptional repressor and behaves as a putative tumor suppressor in different types of cancer. Using gene expression profiling, we found that transcriptional targets of PRDM5 in human U2OS cells include critical genes involved in developmental processes, and specifically in regulating wnt signaling. We therefore assessed PRDM5 function in vivo by performing loss-of-function and gain-of-function experiments in zebrafish embryos. Depletion of prdm5 resulted in impairment of morphogenetic movements during gastrulation and increased the occurrence of the masterblind phenotype in axin+/− embryos, characterized by the loss of eyes and telencephalon. Overexpression of PRDM5 mRNA had opposite effects on the development of anterior neural structures, and resulted in embryos with a shorter body axis due to posterior truncation, a bigger head and abnormal somites. In situ hybridization experiments aimed at analyzing the integrity of wnt pathways during gastrulation at the level of the prechordal plate revealed inhibition of non canonical PCP wnt signaling in embryos overexpressing PRDM5, and over-activation of wnt/β-catenin signaling in embryos lacking Prdm5. Our data demonstrate that PRDM5 regulates the expression of components of both canonical and non canonical wnt pathways and negatively modulates wnt signaling in vivo

Myc-regulated microRNAs attenuate embryonic stem cell differentiation

Myc proteins are known to have an important function in stem cell maintenance. As Myc has been shown earlier to regulate microRNAs (miRNAs) involved in proliferation, we sought to determine whether c-Myc also affects embryonic stem (ES) cell maintenance and differentiation through miRNAs. Using a quantitative primer-extension PCR assay we identified miRNAs, including, miR-141, miR-200, and miR-429 whose expression is regulated by c-Myc in ES cells, but not in the differentiated and tumourigenic derivatives of ES cells. Chromatin immunoprecipitation analyses indicate that in ES cells c-Myc binds proximal to genomic regions encoding the induced miRNAs. We used expression profiling and seed homology to identify genes specifically downregulated both by these miRNAs and by c-Myc. We further show that the introduction of c-Myc-induced miRNAs into murine ES cells significantly attenuates the downregulation of pluripotency markers on induction of differentiation after withdrawal of the ES cell maintenance factor LIF. In contrast, knockdown of the endogenous miRNAs accelerate differentiation. Our data show that in ES cells c-Myc acts, in part, through a subset of miRNAs to attenuate differentiation

Impact of whitefish on Cladocera communities

Introduserte arter har blitt vist å ha effekter på lokal populasjoner både i eksperimenter og i studier av økosystemer. For å kunne ivareta biodiversitet og økosystemtjenester er økt forståelse av menneskelig påvirkning av ferkvann og de tilhørende økosystemene viktig. Paleolimnologiske metoder har fått økt oppmerksomhet med tanke på å kunne forstå effektene av invasive arter siden det tillater å studere systemene i et øko-evolusjonær tidsperspektiv. Sik er en spesialisert zooplanktivor art som har blitt spredt i Røros kommune etter at bosetninger ble etablert som et resultat av gruveindustrien. Ved å sammeligne Cladocera forekomster i innsjøer med sik fraværende og tilstedværende kan vi økte forståelsen av introduserte arters effekter på byttedyr sammfunn. Denne studien fant ingen effekt i forekomst for 12 av 13 analyserte slekter i ordenen Cladocera. En slekt (Alonella) viste en reduksjon som følge av sik, motsatt av hva størrelse effektivitet hypothesen predikerer. Tidligere studier og eksperimenter har vist at en reduksjon i større Cladocera arter forventes. Funnene presentert her gir grunn til å tro at sik ikke representerer en betraktlig trussel for forekomstene hos Cladocera. Potensielle forklaringer på hvorfor ingen betraktlige forskjeller blir observert til tross for sik tilstedeværesle eller fravær blir diskutert. Videre studier som kan forklare responsene hos Cladocera som følge av utsetting av sik annbefales

A Model of Trade Wars

The dissertation offers a theoretical model of why countries engage in trade wars. The underlying aim is to understand the current US-China trade war. Existing oligopolistic competition models explain tariffs as beggar-thy-neighbour policies. Countries have an individual interest in levying tariffs to capture some of the profits of other countries. However, when all countries do this, they are worse off than under mutual free trade. This explanation makes sense in most cases of trade barriers. However, it offers an incomplete understanding of trade between countries that pose a security threat to each other. Drawing on insights from political science, I argue that the economic surplus created by trade has potential security implications. This is because countries can use the surplus to invest in military capabilities, which they might deploy against each other in a future war. Wars between two countries can at most have one winner. Accordingly, when countries that pose a security threat to each other set tariff rates, they need to consider the security implications: how does trade impact their relative ability to invest in military capabilities? I model tariff setting when trade has security implications with a two-country duopoly. Both countries have one firm that operates in both markets, selling an undifferentiated good under Cournot quantity competition. I assume that both countries put given weights on the social welfare gains from trade and security concerns when setting tariffs. I solve the model for the Nash tariff. Two main findings follow from my model. First, the more weight countries put on security concerns, the higher the Nash tariffs become. Second, in an iterated prisoner's dilemma, more weight on security concerns decreases the set where it is possible to sustain free trade. Moreover, even when sustaining free trade is possible, the discount factor necessary to do this is higher. The model offers a plausible explanation of the outbreak of the US-China trade war. National Security Strategy documents reveal that the Trump administration saw China as a bigger security threat than previous administrations, and accordingly put more weight on security concerns. This shifted the US-China relationship from a free trade to a tariff equilibrium. My model also helps to explain why, at the time of writing, there is no end in sight to the trade war, despite the clear negative impact it has had on both sides