Significance of glucose-regulated protein GRP170 (ORP150) in mouse striatal development

Abstract

The glucose-regulated protein 170 (Grp 170) is a nucleotide exchange factor for Grp78 and they are resident of endoplasmic reticulum (ER). Grp 170 expresses highly in the brain and removal of Grp 170 from the whole body leads to mouse embryonic lethality. Grp170 protein is overexpressed after many cellular stressors and has protective function in neural, renal and cardiac models of ischemia and reperfusion. To understand the function of Grp 170 in the brain, we have generated a conditional knockout of Grp 170 in mice. We used Nestin Cre recombinase transgenic mice crossed with Grp 170Flox Flox mice to generate Grp 170Flox Flox -Nestin-Cre+ mice, which died upon birth. Therefore, we analyzed Grpl70Flox. Flox -Nestin-Cre+ embryos between embryonic days El3.5 day to El8.5 to determine the function ofGrp170 during brain development. Our data indicate that CNS cell population expressing Cre recombinase efficiently deletes Grpl70 at E13.5 day and brain appears normal at this stage. However, at El4.5 to E18.5, there is a significant loss of neuronal cells in the developing striatum and a decrease in brain anatomical size and increase in the lateral ventricle volume in the absence of Grp 170. Thus, we hypothesize that Grp 170 facilitates proper folding and ER transport of one or more key polypeptide molecule(s) involved in neuronal cell survival in the developing striatum. Interestingly, expression of Grp78 is significantly enhanced in the cortex, striatum and midbrain suggesting the presence of ER stress in cells lacking Grp 170 in the developing mice.