This
transmembrane protein is responsible for the
influx of
zinc,
manganese,
iron, and
cadmium.[8] ZIP8 is distributed among the
embryo,
placenta, and
yolk sac during development.[9] Within the embryo, the concentration of ZIP8 is highest during the developmental period of different organ systems, specifically the heart where is it localized in the
endothelial cells.
Cardiac development is a zinc-dependent event. Beginning around mouse E8.0, the heart is in a tubular form with an outer
myocardium layer and an inner
endocardium layer, separated by cardiac jelly.[10] As development continues, trabeculation, the
protrusion of
cardiomyocytes into the cardiac jelly, begins and facilitates nutrient and oxygen exchange prior to the establishment of
coronary vessels. Simultaneous with coronary circulation development, the
trabeculae then collapse into the ventricular wall in a process known as
compaction.
Cardiomyocyte differentiation,
proliferation, and trabeculae patterning is regulated through
Notch 1signaling, which is upregulated by the ECM.
ADAMTS1,
5,
7, 15, and 19 are zinc
metalloenzymes responsible for degrading the ECM prior to compaction.[11] Many studies have analyzed the effects of Slc39a8-/- on fetal heart development and have shown a decrease in
zinc influx leading to an increase in
cardiomyocyte proliferation through
BMP10, hypertrabeculation through the upregulation of Notch1, and ventricular non-compaction due to the persistence of the ECM.