ABSTRACT Maintenance of normal hematopoiesis depends on developmental programs for the hematopoietic stem and progenitor cell (HSPC). Still, these programs require guidance by cell-extrinsic mechanisms that correctly convey the dynamically changing needs of the blood cells. Our prior work established that the hepatocyte-specific Ashwell-Morell receptor (AMR), a multimeric endocytic receptor, binds to aged platelets, inducing JAK-STAT signaling and production of thrombopoietin (TPO), the cytokine responsible for megakaryocyte maturation and differentiation, platelet production, and maintenance of HSPCs. In addition to regulating TPO production and removing aged platelets, we uncovered an unexpected mechanism by which the AMR regulates erythropoiesis. Our preliminary data suggest a role for the hepatic AMR in regulating Neuregulin 4 (Nrg4) levels, the specific ligand for ErbB4 (also known as HER4), the fourth member of the receptor tyrosine kinase family that includes the epidermal growth factor (EGF) receptor (EGFR/HER1), ErbB2/HER2, and ErbB3/HER3. A genome-wide association study (GWAS) shows that NRG4 variants are associated with changes in hemoglobin levels, and ErbB4 signaling contributes to human and mouse erythropoiesis. Our data shows that an increase in Nrg4 affects ErbB4 expression and signaling in bone marrow mesenchymal stem cells (MSCs), leading to defective erythropoiesis and increased expression levels of S100a8 and S100a9, members of the calcium-binding S100 protein family, known as Calgranulin A and B, respectively. Recombinant, extracellular, and increased S100a8 expression levels in erythrocyte progenitors induce an erythroid differentiation defect. We seek to define how Nrg4/ErbB4 affects HSPC homeostasis and erythropoiesis, including erythroblastic islands (Aim 1). We will interrogate the mechanism by which Nrg4/ErbB4 affect MSC function, calgranulin expression, and erythropoiesis (Aim 2). We use a multipronged approach of genetic mouse modeling, inhibitors, transcriptomics, and biochemical approaches to allow mechanistic exploration into the participation of the Nrg4/ErbB4/calgranulin axis in contributing to erythropoiesis. The proposed investigation will further drive therapeutic development to ameliorate erythropoietic deficiencies in blood disease, including in patients with myeloproliferative neoplasms and myelodysplastic syndrome.