title: Mice lacking microRNAs in Pax8-expressing cells develop hypothyroidism and end-stage renal failure.
abstract: BACKGROUND
  Non-coding RNAs have gained increasing attention during the last decade. The first large group of non-coding RNAs to be characterized systematically starting at the beginning of the 21st century were small oligonucleotides--the so-called microRNAs (miRNAs). By now we have learnt that microRNAs are indispensable for most biological processes including organogenesis and maintenance of organ structure and function. The role of microRNAs has been studied extensively in the development of a number of organs, so far most studies focussed on e.g. the heart or the brain whilst the role of microRNAs in the development and maintenance of complex epithelial organs is less well understood. Furthermore most analyses regarding microRNA function in epithelial organs employed conditional knockout mouse models of the RNAse III Dicer to abrogate microRNA biogenesis. However, there is increasing evidence for Dicer to have multiple functions independent from microRNA maturation. Therefore Dicer independent models are needed to gain further insight into the complex biology of miRNA dependent processes.
  
  
  RESULTS
  Here we analyze the contribution of microRNA-dependent transcriptional control in Pax8-expressing epithelial cells. Pax8 is a transcription factor that is crucial to the development of epithelial organs. The miRNA machinery was disrupted by crossing conditional DiGeorge syndrome critical region 8 (Dgcr8) fl/fl mice to Pax8Cre mice. The Dgcr8/Drosha complex processes pri-miRNAs in the nucleus before they are exported as pre-miRNAs for further maturation by Dicer in the cytoplasm. Dgcr8 fl/fl; Pax8Cre+ knockout mice died prematurely, developed massive hypothyroidism and end stage renal disease due to a loss of miRNAs in Pax8 expressing tissue.
  
  
  CONCLUSIONS
  Pax8Cre-mediated conditional loss of DiGeorge syndrome critical region 8 (Dgcr8), an essential component of the nuclear machinery that is required for microRNA biogenesis, resulted in severe hypothyroidism, massively reduced body weight and ultimately led to renal failure and death of the animals. These data provide further insight into the importance of miRNAs in organ homeostasis using a Dicer independent model.
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.
authors.forename: Malte P
authors.initials: MP
authors.lastname: Bartram
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli 'Federico II', Naples, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Amendola
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.|Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Benzing
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany.|Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany.
authors.forename: Bernhard
authors.initials: B
authors.lastname: Schermer
authors.affiliation: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Università degli Studi di Napoli 'Federico II', Naples, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: de Vita
authors.affiliation: Department II of Internal Medicine and Center for Molecular Medicine, University of Cologne, Kerpener Str. 62, 50937, Cologne, Germany. roman-ulrich.mueller@uk-koeln.de.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases, University of Cologne, Cologne, Germany. roman-ulrich.mueller@uk-koeln.de.|Systems Biology of Ageing Cologne, University of Cologne, Cologne, Germany. roman-ulrich.mueller@uk-koeln.de.
authors.forename: Roman-Ulrich
authors.initials: RU
authors.lastname: Müller
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D007037:Hypothyroidism / Q000235:genetics* / Q000473:pathology; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007676:Kidney Failure, Chronic / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010641:Phenotype
chemical_list: D035683:MicroRNAs; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; C499496:Pax8 protein, mouse
keywords: CAKUT; Cystic kidney disease; Dgcr8; Dicer; Hydronephrosis; Kidney; MiRNA; Pax8; Thyroid gland