title: Miz1 deficiency in the mammary gland causes a lactation defect by attenuated Stat5 expression and phosphorylation.
abstract: Miz1 is a zinc finger transcription factor with an N-terminal POZ domain. Complexes with Myc, Bcl-6 or Gfi-1 repress expression of genes like Cdkn2b (p15(Ink4)) or Cdkn1a (p21(Cip1)). The role of Miz1 in normal mammary gland development has not been addressed so far. Conditional knockout of the Miz1 POZ domain in luminal cells during pregnancy caused a lactation defect with a transient reduction of glandular tissue, reduced proliferation and attenuated differentiation. This was recapitulated in vitro using mouse mammary gland derived HC11 cells. Further analysis revealed decreased Stat5 activity in Miz1ΔPOZ mammary glands and an attenuated expression of Stat5 targets. Gene expression of the Prolactin receptor (PrlR) and ErbB4, both critical for Stat5 phosphorylation (pStat5) or pStat5 nuclear translocation, was decreased in Miz1ΔPOZ females. Microarray, ChIP-Seq and gene set enrichment analysis revealed a down-regulation of Miz1 target genes being involved in vesicular transport processes. Our data suggest that deranged intracellular transport and localization of PrlR and ErbB4 disrupt the Stat5 signalling pathway in mutant glands and cause the observed lactation phenotype.
authors.affiliation: Department of Cytobiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Adrián
authors.initials: A
authors.lastname: Sanz-Moreno
authors.affiliation: Department of Cytobiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Fuhrmann
authors.affiliation: Theodor-Boveri-Institute, Biocentre, University of Würzburg, Würzburg, Germany.
authors.forename: Elmar
authors.initials: E
authors.lastname: Wolf
authors.affiliation: Theodor-Boveri-Institute, Biocentre, University of Würzburg, Würzburg, Germany.
authors.forename: Björn
authors.initials: B
authors.lastname: von Eyss
authors.affiliation: Theodor-Boveri-Institute, Biocentre, University of Würzburg, Würzburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Eilers
authors.affiliation: Department of Cytobiology, Philipps-University Marburg, Marburg, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Elsässer
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015536:Down-Regulation / Q000235:genetics; D005260:Female; D007775:Lactation Disorders / Q000235:genetics* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000235:genetics*; D010766:Phosphorylation; D011247:Pregnancy; D050828:Protein Inhibitors of Activated STAT / Q000235:genetics*; D011494:Protein Kinases / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000235:genetics; D050799:STAT5 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
chemical_list: D009687:Nuclear Proteins; D050828:Protein Inhibitors of Activated STAT; D050799:STAT5 Transcription Factor; C485521:Miz1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D011494:Protein Kinases