Effect of constitutive Rs1-mediated G_s signaling in OBCs on hematopoiesis. Model summarizing the extensive changes in the bone and BM stromal of ColI(2.3)⁺/Rs1⁺ (Rs1) mice and their consequences for HSC maintenance and blood development. OBC-specific expression of Rs1 increases G_s signaling and expands the number of immature osteoblasts leading to increased trabecular bone formation. This also results indirectly in increased numbers of MSCs and ECs. Together, these expanded BM stromal cells restrict the space available for hematopoietic cells and lead to BM aplasia, which is not compensated by extramedullary hematopoiesis. Increased G_s signaling in Rs1-expressing OBCs decreases their expression of key HSC-maintenance genes, including Cxcl12, Angpt1, and Vcam1, and impairs their HSC-supportive function leading to a severe loss of HSC numbers. Rs1 mice also show diminished production of megakaryocyte and erythrocyte progenitors through a mechanism that still largely remains to be elucidated but involves decreased levels of circulating Tpo. As a consequence, Rs1 mice have impaired regenerative potential after acute injury but overall preserved blood function probably because of the contribution of splenic hematopoiesis.