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National Institute of Environmental Health Sciences

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Publication Detail

Title: In utero gene expression in the Slc39a8(neo/neo) knockdown mouse.

Authors: Chen, Jing; Gálvez-Peralta, Marina; Zhang, Xiang; Deng, Jingyuan; Liu, Zijuan; Nebert, Daniel W

Published In Sci Rep, (2018 Jul 16)

Abstract: Slc39a8 encodes ZIP8, a divalent cation/bicarbonate symporter expressed in pluripotent mouse embryonic stem cells, and therefore ubiquitous in adult tissues; ZIP8 influxes Zn2+, Mn2+ and Fe2+. Slc39a8(neo/neo) knockdown mice exhibit 10-15% of wild-type ZIP8 mRNA and protein levels, and show pleiotropic phenotype of stunted growth, neonatal lethality, multi-organ dysmorphogenesis, and dysregulated hematopoiesis manifested as severe anemia. Herein we performed RNA-seq analysis of gestational day (GD)13.5 yolk sac and placenta, and GD16.5 liver, kidney, lung, heart and cerebellum, comparing Slc39a8(neo/neo) with Slc39a8(+/+) wild-type. Meta-data analysis of differentially-expressed genes revealed 29 unique genes from all tissues - having enriched GO categories associated with hematopoiesis and hypoxia and KEGG categories of complement, response to infection, and coagulation cascade - consistent with dysregulated hematopoietic stem cell fate. Based on transcription factor (TF) profiles in the JASPAR database, and searching for TF-binding sites enriched by Pscan, we identified numerous genes encoding zinc-finger and other TFs associated with hematopoietic stem cell functions. We conclude that, in this mouse model, deficient ZIP8-mediated divalent cation transport affects zinc-finger (e.g. GATA proteins) and other TFs interacting with GATA proteins (e.g. TAL1), predominantly in yolk sac. These data strongly support the phenotype of dysmorphogenesis and anemia seen in Slc39a8(neo/neo) mice in utero.

PubMed ID: 30013175 Exiting the NIEHS site

MeSH Terms: Anemia/genetics*; Animals; Cation Transport Proteins/deficiency*; Disease Models, Animal; Embryo, Mammalian; Female; GATA Transcription Factors/metabolism*; Gene Expression Profiling; Gene Expression Regulation, Developmental*; Gene Knockdown Techniques; Hematopoiesis/genetics; Hematopoietic Stem Cells/metabolism*; Humans; Male; Mice; Mice, Transgenic; Morphogenesis/genetics; Mouse Embryonic Stem Cells/metabolism; Pregnancy; Sequence Analysis, RNA; T-Cell Acute Lymphocytic Leukemia Protein 1/metabolism; Yolk Sac/cytology; Yolk Sac/metabolism; Zinc Fingers

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