PMID- 22563477
OWN - NLM
STAT- MEDLINE
DCOM- 20120921
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 5
DP  - 2012
TI  - ZIP8 zinc transporter: indispensable role for both multiple-organ organogenesis 
      and hematopoiesis in utero.
PG  - e36055
LID - 10.1371/journal.pone.0036055 [doi]
LID - e36055
AB  - Previously this laboratory characterized Slc39a8-encoded ZIP8 as a 
      Zn(2+)/(HCO(3)(-))(2) symporter; yet, the overall physiological importance of 
      ZIP8 at the whole-organism level remains unclear. Herein we describe the 
      phenotype of the hypomorphic Slc39a8(neo/neo) mouse which has retained the 
      neomycin-resistance gene in intron 3, hence causing significantly decreased ZIP8 
      mRNA and protein levels in embryo, fetus, placenta, yolk sac, and several tissues 
      of neonates. The Slc39a8(neo) allele is associated with diminished zinc and iron 
      uptake in mouse fetal fibroblast and liver-derived cultures; consequently, 
      Slc39a8(neo/neo) newborns exhibit diminished zinc and iron levels in several 
      tissues. Slc39a8(neo/neo) homozygotes from gestational day(GD)-11.5 onward are 
      pale, growth-stunted, and die between GD18.5 and 48 h postnatally. Defects 
      include: severely hypoplastic spleen; hypoplasia of liver, kidney, lung, and 
      lower limbs. Histologically, Slc39a8(neo/neo) neonates show decreased numbers of 
      hematopoietic islands in yolk sac and liver. Low hemoglobin, hematocrit, red cell 
      count, serum iron, and total iron-binding capacity confirmed severe anemia. Flow 
      cytometry of fetal liver cells revealed the erythroid series strikingly affected 
      in the hypomorph. Zinc-dependent 5-aminolevulinic acid dehydratase, required for 
      heme synthesis, was not different between Slc39a8(+/+) and Slc39a8(neo/neo) 
      offspring. To demonstrate further that the mouse phenotype is due to ZIP8 
      deficiency, we bred Slc39a8(+/neo) with BAC-transgenic BTZIP8-3 line (carrying 
      three extra copies of the Slc39a8 allele); this cross generated viable 
      Slc39a8(neo/neo)_BTZIP8-3(+/+) pups showing none of the above-mentioned 
      congenital defects-proving Slc39a8(neo/neo) causes the described phenotype. Our 
      study demonstrates that ZIP8-mediated zinc transport plays an unappreciated 
      critical role during in utero and neonatal growth, organ morphogenesis, and 
      hematopoiesis.
FAU - Galvez-Peralta, Marina
AU  - Galvez-Peralta M
AD  - Department of Environmental Health, University of Cincinnati Medical Center, 
      Cincinnati, Ohio, United States of America.
FAU - He, Lei
AU  - He L
FAU - Jorge-Nebert, Lucia F
AU  - Jorge-Nebert LF
FAU - Wang, Bin
AU  - Wang B
FAU - Miller, Marian L
AU  - Miller ML
FAU - Eppert, Bryan L
AU  - Eppert BL
FAU - Afton, Scott
AU  - Afton S
FAU - Nebert, Daniel W
AU  - Nebert DW
LA  - eng
GR  - P30 ES006096/ES/NIEHS NIH HHS/United States
GR  - R01 ES010416/ES/NIEHS NIH HHS/United States
GR  - T32 ES016646/ES/NIEHS NIH HHS/United States
GR  - P30 ES06096/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20120501
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Cation Transport Proteins)
RN  - 0 (Slc39a8 protein, mouse)
RN  - J41CSQ7QDS (Zinc)
SB  - IM
MH  - Animals
MH  - Animals, Newborn
MH  - Biological Transport
MH  - Blotting, Western
MH  - Cation Transport Proteins/genetics/metabolism/*physiology
MH  - Cells, Cultured
MH  - Embryo, Mammalian/cytology/*embryology/metabolism
MH  - Female
MH  - Fibroblasts/metabolism
MH  - Gene Expression Regulation, Developmental
MH  - Hematopoiesis/genetics/*physiology
MH  - Liver/cytology/embryology/metabolism
MH  - Male
MH  - Mice
MH  - Mice, 129 Strain
MH  - Mice, Inbred C57BL
MH  - Mice, Knockout
MH  - Mice, Transgenic
MH  - Organogenesis/genetics/*physiology
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Yolk Sac/embryology/metabolism
MH  - Zinc/metabolism
PMC - PMC3341399
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/05/09 06:00
MHDA- 2012/09/22 06:00
PMCR- 2012/05/01
CRDT- 2012/05/08 06:00
PHST- 2011/02/12 00:00 [received]
PHST- 2012/03/29 00:00 [accepted]
PHST- 2012/05/08 06:00 [entrez]
PHST- 2012/05/09 06:00 [pubmed]
PHST- 2012/09/22 06:00 [medline]
PHST- 2012/05/01 00:00 [pmc-release]
AID - PONE-D-11-03059 [pii]
AID - 10.1371/journal.pone.0036055 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(5):e36055. doi: 10.1371/journal.pone.0036055. Epub 2012 May 1.