zip8 zinc transporter indispensable role for both multiple-organ organogenesis and hematopoiesis in uterozip8锌转运体不可或缺的角色对多个器官器官形成,在子宫内造血作用.pdf

ZIP8 Zinc Transporter: Indispensable Role for Both Multiple-Organ Organogenesis and Hematopoiesis In Utero ´ 1 1¤a 1 1¤b 1 Marina Galvez-Peralta , Lei He , Lucia F. Jorge-Nebert , Bin Wang , Marian L. Miller , 1 2 1 Bryan L. Eppert , Scott Afton , Daniel W. Nebert * 1 Department of Environmental Health, and Center for Environmental Genetics (CEG), University of Cincinnati Medical Center, Cincinnati, Ohio, United States of America, 2 Department of Chemistry, University Cincinnati School of Arts and Sciences, Cincinnati, Ohio, United States of America Abstract Previously this laboratory characterized Slc39a8-encoded ZIP8 as a Zn2+/(HCO3–)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, r