1. Department of Genetics and
2. Department of Cell Biology and Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan
3. Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan
4. Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan
5. Sakura Motion Picture Co. Ltd, 20-1 Sendagaya 4-chome, Shibuya, Tokyo 151-0051, Japan

Correspondence to: Shigekazu Nagata^1,3,4 Correspondence and requests for materials should be addressed to S.N. (Email: Nagata@genetic.med.osaka-u.ac.jp).

Abstract

Definitive erythropoiesis usually occurs in the bone marrow or fetal liver, where erythroblasts are associated with a central macrophage in anatomical units called 'blood islands'^{1, 2}. Late in erythropoiesis, nuclei are expelled from the erythroid precursor cells and engulfed by the macrophages in the blood island^{2, 3}. Here we show that the nuclei are engulfed by macrophages only after they are disconnected from reticulocytes, and that phosphatidylserine, which is often used as an 'eat me' signal for apoptotic cells, is also used for the engulfment of nuclei expelled from erythroblasts. We investigated the mechanism behind the enucleation and engulfment processes by isolating late-stage erythroblasts from the spleens of phlebotomized mice. When these erythroblasts were cultured, the nuclei protruded spontaneously from the erythroblasts. A weak physical force could disconnect the nuclei from the reticulocytes. The released nuclei contained an undetectable level of ATP, and quickly exposed phosphatidylserine on their surface. Fetal liver macrophages efficiently engulfed the nuclei; masking the phosphatidylserine on the nuclei with the dominant-negative form of milk-fat-globule EGF8 (MFG-E8) prevented this engulfment.

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