First name
Cinzia
Last name
Milesi
Year of Study
Research Center
Thesis Title
Redundant And Non-Redundant Roles Of The Endocytic Adaptor Proteins Eps15 And Eps15l1 In Mammals
Thesis Abstract
Eps15 and Eps15L1 are two homologous endocytic adaptor proteins that have been involved in endocytosis of several plasma membrane receptors through in vitro studies on cell lines.
Eps15 knockout (KO) mice are healthy and fertile, while Eps15L1-KO mice die at birth presumably because of neural defects. Importantly, Eps15/Eps15L1 double knockout (DKO) mice have a more severe phenotype, dying at midgestation, suggesting redundancy of the two proteins in one or more fundamental developmental programs.
The aim of this thesis project was to investigate redundant and non-redundant roles of Eps15 and Eps15L1, with the final goal to unmask the underlying causes of embryonic lethality of Eps15/Eps15L1-DKO mice.
Since Eps15/Eps15L1-DKO mice displayed a Notch loss-of-function phenotype, we hypothesized that Eps15 and Eps15L1 redundantly regulated Notch signalling. Using mouse embryonic fibroblasts as signal-sending cells in a co-culture model system, we found that Eps15L1 non-redundantly activated Notch signalling. This finding indicated that impaired Notch signalling only partially contributed to the DKO phenotype.
Since Eps15/Eps15L1-DKO mice were pale, we hypothesized that Eps15 and Eps15L1 redundantly regulated erythropoiesis. Analysis of conditional Eps15/Eps15L1-DKO mice, lacking Eps15 and Eps15L1 in hematopoietic cells, revealed that these mice survived to adulthood but suffered from microcytic hypochromic anemia. Our data suggest that impaired erythropoiesis might be linked to a redundant role of Eps15 and Eps15L1 in the regulation of endocytosis of the transferrin receptor in red blood cells.
Our findings indicate that Eps15 and Eps15L1 regulate several developmental programs, some non-redundantly and others redundantly, possibly addictively contributing to the DKO phenotype.
Eps15 knockout (KO) mice are healthy and fertile, while Eps15L1-KO mice die at birth presumably because of neural defects. Importantly, Eps15/Eps15L1 double knockout (DKO) mice have a more severe phenotype, dying at midgestation, suggesting redundancy of the two proteins in one or more fundamental developmental programs.
The aim of this thesis project was to investigate redundant and non-redundant roles of Eps15 and Eps15L1, with the final goal to unmask the underlying causes of embryonic lethality of Eps15/Eps15L1-DKO mice.
Since Eps15/Eps15L1-DKO mice displayed a Notch loss-of-function phenotype, we hypothesized that Eps15 and Eps15L1 redundantly regulated Notch signalling. Using mouse embryonic fibroblasts as signal-sending cells in a co-culture model system, we found that Eps15L1 non-redundantly activated Notch signalling. This finding indicated that impaired Notch signalling only partially contributed to the DKO phenotype.
Since Eps15/Eps15L1-DKO mice were pale, we hypothesized that Eps15 and Eps15L1 redundantly regulated erythropoiesis. Analysis of conditional Eps15/Eps15L1-DKO mice, lacking Eps15 and Eps15L1 in hematopoietic cells, revealed that these mice survived to adulthood but suffered from microcytic hypochromic anemia. Our data suggest that impaired erythropoiesis might be linked to a redundant role of Eps15 and Eps15L1 in the regulation of endocytosis of the transferrin receptor in red blood cells.
Our findings indicate that Eps15 and Eps15L1 regulate several developmental programs, some non-redundantly and others redundantly, possibly addictively contributing to the DKO phenotype.
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