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OLA1, an Obg-family GTPase, has been implicated in eukaryotic initiation factor 2 (eIF2)-mediated translational control, but its physiological functions remain obscure. Here we report that mouse embryos lacking OLA1 have stunted growth, delayed development leading to immature organs-especially lungs-at birth, and frequent perinatal lethality. Proliferation of primary Ola1(-/-) mouse embryonic fibroblasts (MEFs) is impaired due to defective cell cycle progression, associated with reduced cyclins D1 and E1, attenuated Rb phosphorylation, and increased p21(Cip1/Waf1) Accumulation of p21 in Ola1(-/-) MEFs is due to enhanced mRNA translation and can be prevented by either reconstitution of OLA1 expression or treatment with an eIF2α dephosphorylation inhibitor, suggesting that OLA1 regulates p21 through a translational mechanism involving eIF2. With immunohistochemistry, overexpression of p21 protein was detected in Ola1-null embryos with reduced cell proliferation. Moreover, we have generated p21(-/-) Ola1(-/-) mice and found that knockout of p21 can partially rescue the growth retardation defect of Ola1(-/-) embryos but fails to rescue them from developmental delay and the lethality. These data demonstrate, for the first time, that OLA1 is required for normal progression of mammalian development. OLA1 plays an important role in promoting cell proliferation at least in part through suppression of p21 and organogenesis via factors yet to be discovered.

OLA1, a Translational Regulator of p21, Maintains Optimal Cell Proliferation Necessary for Developmental Progression