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Download (4MB) DISSERTATION submitted to the Combined Faculties for the Natural Sciences and for Mathematics of the Ruperto-Carola University of Heidelberg, Germany for the degree of Doctor of Natural Sciences presented by M.Sc. Daniela Casarrubea born in Palermo (Italy) Oral examination: 1st February 2013 A NEW MOUSE MODEL WITH GAIN OF IRON REGULATORY PROTEIN 1 FUNCTION Referees: 1. Dr. Darren Gilmour 2. Prof. Dr. Klaus Unsicker SUMMARY SUMMARY Disorders of iron metabolism account for some of the most common human diseases, such as anemias and hemochromatosis. To maintain physiological iron balance, homeostatic mechanisms are normally in place both at the systemic and the cellular level. Cellular iron homeostasis is secured by Iron Regulatory Proteins (IRP) −1 and −2 through their binding to cis- regulatory iron-responsive elements (IRE) in target mRNAs encoding proteins with key functions in iron metabolism. In turn, the IRE−binding activity of the two IRPs is feedback regulated by the cellular labile iron pool. Mouse models with IRP deficiency have contributed valuable insights into the in vivo roles of the IRP/IRE system as well as mammalian iron biology. However, the physiological consequences of gain of IRP function have so far remained unexplored. To investigate the importance of adequate IRP expression in vivo, we have generated a mouse model allowing conditional gain of IRP function using Cre/Lox technology. This new line expresses a flag-tagged IRP1 mutant (IRP1*), which escapes iron-mediated regulation, being constitutively active in its IRE binding form. Systemic expression of the IRP1* transgene from the Rosa26 locus yields viable animals with gain of IRE-binding activity in all organs that were analyzed. IRP1* alters the expression of IRP target genes and is accompanied by abnormal body iron distribution. Furthermore, mice display macrocytic erythropenia with decreased hematocrit and hemoglobin levels. Flow cytometric analysis of bone marrow-derived erythroid precursors also revealed impaired erythroid differentiation. Under standard laboratory conditions, broad spectrum phenotyping of IRP1* mice revealed that gain of IRP1 function does not affect their general health status. Yet, when challenged, mice displayed mildly altered motor coordination and reduced endurance as well as impaired neuromuscular transmission, suggesting a potential role of appropriate IRP activity in maintenance of neuromuscular function. Ex vivo, iron challenged bone marrow-derived macrophages showed that IRP1* expression alters the cellular response to fluctuations in iron levels. However, when IRP1* mice were pharmacologically administered with iron or crossed with a mouse model of chronic iron overload, IRP1* expression did not produce any overt abnormalities in the animal response to the iron challenges. In conclusion, this work describes the first model of gain of IRP1 function in a mammalian organism. This new mouse model further highlights the importance of appropriate IRP regulation in central organs of iron metabolism as well as for general physiology. Moreover, it opens novel avenues for study of diseases associated with abnormally high IRP activity, such as Parkinson’s disease or Friedreich ataxia. ZUSAMMENFASSUNG ZUSAMMENFASSUNG Ein neues Mausmodell mit erhöhter Aktivität des Iron Regulatory Protein 1 Störungen des Eisenstoffwechsels sind für einige der häufigsten Krankheiten des Menschen verantwortlich, wie etwa der Anämie und der Hämochromatose. Um eine physiologische Eisenbalance zu gewährleisten, spielen homöostatische Mechanismen sowohl auf der systemischen wie auch auf der zellulären Ebene eine wichtige Rolle. Dabei wird die zelluläre Eisenhomöostase durch zwei Proteine, Iron Regulatory Proteins (IRP -1 und -2), vermittelt. Dies geschieht durch IRP-Bindung an cis-regulatorische Elemente, iron responsive elements (IRE), in mRNAs die für Proteine kodieren, die ihrerseits Schlüsselfunktionen im Eisenstoffwechsel einnehmen. Gleichzeitig wird die IRE-bindende Aktivität der beiden IRPs mittels eines feedback Mechanismus durch den verfügbaren Eisenpool der Zelle reguliert. IRP-defizente Mausmodelle konnten bereits wertvolle Einblicke in die Rolle des IRP/IRE Systems in vivo und in die RNA- Biologie von Säugetieren geben. Auf der anderen Seite blieben die physiologischen Konsequenzen einer erhöhten IRP Aktivität bislang weitgehend unbekannt. Zur Erforschung des Einflusses einer adäquaten IRP Expression in vivo haben wir ein Mausmodell generiert, das eine konditional erhöhte IRP Aktivität durch Cre/Lox Technologie ermöglicht. Diese neue Mauslinie exprimiert eine mit dem Flag Peptid versehene IRP1 Mutante (IRP1*), die unabhängig vom Eisenstatus konstitutiv in ihrer IRE bindenden Form vorliegt. Systemische Expression des in den Rosa26 Locus integrierten IRP1* Transgen führt zur Überexpression IRE-bindender Aktivität in allen analysierten Organen. IRP1* verändert die Expression von IRP regulierten Genen und führt zu einer anomalen Verteilung des Eisens im Körper. Ausserdem zeigen diese Mäuse eine makrozytäre Erythropenie mit erniedrigten Hämatokrit- und Hämoglobinwerten. Durch analytische Durchflusszytrometrie von Erythrozytenvorläufern aus Knochenmarksgewebe entdeckten wir ausserdem eine Einschränkung der Erythrozytendifferenzierung. Unter Standardlaborbedingungen zeigte eine weitangelegte Phänotypisierung der IRP1* Mäuse dass die zusätzliche IRP1* Aktivität keinen generellen Effekt auf ihre Gesundheit hat. Allerdings fanden sich unter Belastungsbedingungen eine leicht verminderte motorische Koordination sowie reduzierte Ausdauer und gestörte neuromuskuläre Signalweiterleitung, was auf eine mögliche Rolle adäquater IRP-Aktivität bei der Aufrechterhaltung von neuromuskulären Funktionen hindeutet. Ex vivo zeigten aus Kochenmark gewonnene und mit Eisen oder Eisenchelatoren behandelte Makrophagen, dass die IRP1* Expression die zelluläre Antwort auf Schwankungen der Eisenverfügbarkeit verändert. Allerdings ZUSAMMENFASSUNG konnten wir beobachten, dass IRP1* Mäuse die IRP1* Expression weder nach pharmakologischer Gabe von Eisen noch nach Kreuzung mit einem Mausmodell chronischer Eisenüberladung zu irgendwelchen offenkundigen Abnormalitäten bei der Reaktion auf wechselnde Eisenkonzentrationen führte. Zusammenfassend beschreibt diese Arbeit das erste Modell gesteigerter IRP1 Aktivität bei einem Säugetier. Dieses neue Mausmodell unterstreicht die Bedeutung der IRP Regulation in zentralen Organen des Eisenstoffwechsels sowie für die generelle Physiologie. Es eröffnet neue Möglichkeiten Krankheiten zu untersuchen, die mit anomal hoher IRP Aktivität verbunden sind, wie zum Beispiel Morbus Parkinson oder die Friedreichsche Ataxie. TABLE OF CONTENTS TABLE OF CONTENTS I. LIST OF FIGURES ..................................................................................V II. LIST OF TABLES.................................................................................VI III. LIST OF ABBREVIATIONS ........................................................... VII 1. INTRODUCTION .................................................................................... 1 1.1 Iron biology............................................................................................................... 1 1.1.1 The light and dark side of iron biochemistry..................................................................1 1.1.2 Disorders of iron metabolism .........................................................................................2 1.2 Systemic iron metabolism......................................................................................... 3 1.2.1 Systemic iron fluxes .......................................................................................................3 1.2.2 Systemic regulation of iron homeostasis: hepcidin ........................................................5 1.3 Cellular iron metabolism........................................................................................... 7 1.3.1 Cellular iron uptake ........................................................................................................7 1.3.2 Cellular iron utilization...................................................................................................9 1.3.3 Cellular iron storage .....................................................................................................10 1.3.4 Cellular iron export.......................................................................................................11 1.4 Regulation of cellular iron metabolism................................................................... 12 1.4.1 The structure of the IREs and the IRPs.........................................................................12 1.4.2 IRP/IRE post-transcriptional regulation of “iron-genes”..............................................14 1.4.3 Regulation of IRP activity ............................................................................................15 1.4.4 Expanding the IRP regulon...........................................................................................16 1.5 The IRP/IRE system in physiology and disease ..................................................... 17 1.5.1 The IRP/IRE system in erythropoiesis..........................................................................18 1.5.2 The IRP/IRE system in duodenal iron absorption ........................................................23 1.5.3 The IRP/IRE system in liver function...........................................................................25
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