Objective To explore the function of unfolded protein response(UPR) in the differentiation of neural cells. Methods In this study, all trans retinoic acid was used to induce the mouse embryonic stem (ES) cells to differentate, immunocytochemistry and RT PCR were adopted to detect the expression of neural specific markers. With this differentiation system derived from ES cells, the expression of UPR molecules was assayed by RT PCR and Western blot respectively. Results Large amount of cells expressing neural tissue specific markers were obtained. With the differentiation of the cells, the expressions of Irel ? declined in different degree in both RA treated and untreated cells, the expression level was lower in RA untreated cells than that in RA treated cells. The expression of Grp78 was up regulated in RA induced cells, however, no increase of the expression of Grp78 could be detected in RA untreated cells.Conclusion RA induced differentiation of ES cells could be used as the neural differentiation model. The expressions of UPR molecules were associated with expressions of neural tissue specific marker molecules, which suggested that UPR signaling might play a role in neural cell differentiation. [