title: The EMT regulator Zeb2/Sip1 is essential for murine embryonic hematopoietic stem/progenitor cell differentiation and mobilization.
abstract: Zeb2 (Sip1/Zfhx1b) is a member of the zinc-finger E-box-binding (ZEB) family of transcriptional repressors previously demonstrated to regulate epithelial-to-mesenchymal transition (EMT) processes during embryogenesis and tumor progression. We found high Zeb2 mRNA expression levels in HSCs and hematopoietic progenitor cells (HPCs), and examined Zeb2 function in hematopoiesis through a conditional deletion approach using the Tie2-Cre and Vav-iCre recombination mouse lines. Detailed cellular analysis demonstrated that Zeb2 is dispensable for hematopoietic cluster and HSC formation in the aorta-gonadomesonephros region of the embryo, but is essential for normal HSC/HPC differentiation. In addition, Zeb2-deficient HSCs/HPCs fail to properly colonize the fetal liver and/or bone marrow and show enhanced adhesive properties associated with increased β1 integrin and Cxcr4 expression. Moreover, deletion of Zeb2 resulted in embryonic (Tie2-Cre) and perinatal (Vav-icre) lethality due to severe cephalic hemorrhaging and decreased levels of angiopoietin-1 and, subsequently, improper pericyte coverage of the cephalic vasculature. These results reveal essential roles for Zeb2 in embryonic hematopoiesis and are suggestive of a role for Zeb2 in hematopoietic-related pathologies in the adult.
authors.affiliation: Vascular Cell Biology Unit, Department for Molecular Biomedical Research, VIB, Ghent, Belgium.
authors.forename: Steven
authors.initials: S
authors.lastname: Goossens
authors.forename: Viktor
authors.initials: V
authors.lastname: Janzen
authors.forename: Sonia
authors.initials: S
authors.lastname: Bartunkova
authors.forename: Tomomasa
authors.initials: T
authors.lastname: Yokomizo
authors.forename: Benjamin
authors.initials: B
authors.lastname: Drogat
authors.forename: Mihaela
authors.initials: M
authors.lastname: Crisan
authors.forename: Katharina
authors.initials: K
authors.lastname: Haigh
authors.forename: Eve
authors.initials: E
authors.lastname: Seuntjens
authors.forename: Lieve
authors.initials: L
authors.lastname: Umans
authors.forename: Tamara
authors.initials: T
authors.lastname: Riedt
authors.forename: Pieter
authors.initials: P
authors.lastname: Bogaert
authors.forename: Lieven
authors.initials: L
authors.lastname: Haenebalcke
authors.forename: Geert
authors.initials: G
authors.lastname: Berx
authors.forename: Elaine
authors.initials: E
authors.lastname: Dzierzak
authors.forename: Danny
authors.initials: D
authors.lastname: Huylebroeck
authors.forename: Jody J
authors.initials: JJ
authors.lastname: Haigh
mesh_terms: D000818:Animals; D015820:Cadherins / Q000378:metabolism; D002454:Cell Differentiation; D002465:Cell Movement; D004622:Embryo, Mammalian / Q000166:cytology* / Q000378:metabolism*; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005434:Flow Cytometry; D005804:Genes, Lethal; D006410:Hematopoiesis / Q000502:physiology*; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism; D018398:Homeodomain Proteins / Q000502:physiology*; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D012097:Repressor Proteins / Q000502:physiology*; D000074165:Zinc Finger E-box Binding Homeobox 2; D016335:Zinc Fingers
chemical_list: D015820:Cadherins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; C120602:ZEB2 protein, mouse; D000074165:Zinc Finger E-box Binding Homeobox 2; C045073:Cre recombinase; D019426:Integrases