3177 – NEURAL CREST CONTRIBUTION TO THE MURINE HSC SPECIFICATION NICHE

Abstract

Hematopoietic stem cells (HSCs) are developmentally specified from endothelium of the dorsal aorta (DA) in the aorta-gonad-mesonephros (AGM) region of the midgestation mouse embryo. Their emergence requires signals from neighboring cell populations in the microenvironment. We previously showed that neural crest cells (NCCs), a migratory population of cells that in mouse migrates to the DA around midgestation, are required for HSC specification in zebrafish. Although NCC-derived differentiated sympathetic neurons have been proposed to promote HSC emergence in the mouse through secretion of catecholamines, an earlier role for NCCs in HSC specification prior to sympathetic neuronal differentiation has not been demonstrated. In the fish model, the NCC requirement precedes sympathetic neuronal differentiation. In our recent studies, we have found that mouse NCCs reach the dorsal aorta between E9.5 and E10 but only express catecholamine-synthesizing enzymes after E10.5, when the definitive hematopoietic program initiates. We hypothesize that NCCs play a role in HSC specification in mouse prior to neuronal differentiation and secretion of catecholamines. To test this possibility, we have used an inducible diphtheria toxin mouse model to ablate NCCs before they reach the DA. Although we find an increase in immature hematopoietic stem and progenitor cells, we note a decrease in pre-HSCs type II. Our data suggest that NCCs play a distinct role in HSC specification at a specific maturational transition point during early specification. Hematopoietic stem cells (HSCs) are developmentally specified from endothelium of the dorsal aorta (DA) in the aorta-gonad-mesonephros (AGM) region of the midgestation mouse embryo. Their emergence requires signals from neighboring cell populations in the microenvironment. We previously showed that neural crest cells (NCCs), a migratory population of cells that in mouse migrates to the DA around midgestation, are required for HSC specification in zebrafish. Although NCC-derived differentiated sympathetic neurons have been proposed to promote HSC emergence in the mouse through secretion of catecholamines, an earlier role for NCCs in HSC specification prior to sympathetic neuronal differentiation has not been demonstrated. In the fish model, the NCC requirement precedes sympathetic neuronal differentiation. In our recent studies, we have found that mouse NCCs reach the dorsal aorta between E9.5 and E10 but only express catecholamine-synthesizing enzymes after E10.5, when the definitive hematopoietic program initiates. We hypothesize that NCCs play a role in HSC specification in mouse prior to neuronal differentiation and secretion of catecholamines. To test this possibility, we have used an inducible diphtheria toxin mouse model to ablate NCCs before they reach the DA. Although we find an increase in immature hematopoietic stem and progenitor cells, we note a decrease in pre-HSCs type II. Our data suggest that NCCs play a distinct role in HSC specification at a specific maturational transition point during early specification.