Notch1 perturbation of hemopoiesis involves non-cell- autonomous modifications.
To study the effects of Notch on hemopoiesis we used a bone marrow transduction/transplantation model and compared the transduced and nontransduced populations in reconstituted mice. While cells expressing a constitutively active form of murine Notch1 (Notch1IC) completely lacked B cells, a profound suppression of the B lineage was also seen in the nontransduced compartment. Experiments performed with retroviral supernatants of varying titers showed that the perturbations of B cell development among the nontransduced population correlated with the percentage of Notch1IC-transduced cells inoculated into the mice. The myeloid lineage of the Notch1IC-transplanted mice was altered as well, and this also affected the nontransduced population that had features of excessive maturation. To explore the basis of these non-cell-autonomous modifications we prepared conditioned medium from ex vivo cultures of Notch1IC-transplanted mice bone marrow and showed that it inhibited B cell maturation and promoted myeloid differentiation in a dose-dependent manner. Finally, we found that the T cell leukemia/lymphomas that occur in Notch1IC-transplanted mice were accompanied by abnormal maturation of nontransduced T cells in the bone marrow. These findings indicate that modifications of neighboring cells through non-cell-autonomous modifications take part in multiple facets of the activity of Notch on hemopoiesis.
Kawamata
Shin
S
SyStemix, Palo Alto, CA 94304, USA.
Du
Changchun
C
Li
Kaijun
K
Lavau
Catherine
C
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D016026:Bone Marrow Transplantation; D002455:Cell Division; D019070:Cell Lineage; D018920:Coculture Techniques; D003114:Colony-Forming Units Assay; D017077:Culture Media, Conditioned / Q000494:pharmacology; D005434:Flow Cytometry; D006410:Hematopoiesis; D016130:Immunophenotyping; D008565:Membrane Proteins / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D009154:Mutation; D023461:Myeloid Progenitor Cells / Q000276:immunology; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D013601:T-Lymphocytes / Q000276:immunology; D014157:Transcription Factors; D014161:Transduction, Genetic
D017077:Culture Media, Conditioned; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors