RT Journal Article SR Electronic T1 Redundant and nonredundant organismal functions of EPS15 and EPS15L1 JF Life Science Alliance JO Life Sci. Alliance FD Life Science Alliance LLC SP e201800273 DO 10.26508/lsa.201800273 VO 2 IS 1 A1 Cinzia Milesi A1 Paola Alberici A1 Benedetta Pozzi A1 Amanda Oldani A1 Galina V Beznoussenko A1 Andrea Raimondi A1 Blanche Ekalle Soppo A1 Stefania Amodio A1 Giusi Caldieri A1 Maria Grazia Malabarba A1 Giovanni Bertalot A1 Stefano Confalonieri A1 Dario Parazzoli A1 Alexander A Mironov A1 Carlo Tacchetti A1 Pier Paolo Di Fiore A1 Sara Sigismund A1 Nina Offenhäuser YR 2019 UL https://www.life-science-alliance.org/content/2/1/e201800273.abstract AB EPS15 and its homologous EPS15L1 are endocytic accessory proteins. Studies in mammalian cell lines suggested that EPS15 and EPS15L1 regulate endocytosis in a redundant manner. However, at the organismal level, it is not known to which extent the functions of the two proteins overlap. Here, by exploiting various constitutive and conditional null mice, we report redundant and nonredundant functions of the two proteins. EPS15L1 displays a unique nonredundant role in the nervous system, whereas both proteins are fundamental during embryo development as shown by the embryonic lethality of -Eps15/Eps15L1-double KO mice. At the cellular level, the major process redundantly regulated by EPS15 and EPS15L1 is the endocytosis of the transferrin receptor, a pathway that sustains the development of red blood cells and controls iron homeostasis. Consequently, hematopoietic-specific conditional Eps15/Eps15L1-double KO mice display traits of microcytic hypochromic anemia, due to a cell-autonomous defect in iron internalization.