Stem cells are thought to balance self-renewal and differentiation through asymmetric and symmetric divisions, but whether such divisions occur during hematopoietic development remains unknown. Using a Notch reporter mouse, in which GFP acts as a sensor for differentiation, we image hematopoietic precursors and show that they undergo both symmetric and asymmetric divisions. In addition we show that the balance between these divisions is not hardwired but responsive to extrinsic and intrinsic cues. Precursors in a prodifferentiation environment preferentially divide asymmetrically, whereas those in a prorenewal environment primarily divide symmetrically. Oncoproteins can also influence division pattern: although BCR-ABL predominantly alters the rate of division and death, NUP98-HOXA9 promotes symmetric division, suggesting that distinct oncogenes subvert different aspects of cellular function. These studies establish a system for tracking division of hematopoietic precursors and show that the balance of symmetric and asymmetric division can be influenced by the microenvironment and subverted by oncogenes.
Bibliographical noteFunding Information:
We are grateful to Brigid Hogan for invaluable help and advice, Mike Dustin for advice on time-lapse microscopy, Gary Gilliland and Craig Jordan for providing the NUP98-HOXA9 construct, Ann Marie Pendergast and Warren Pear for providing the BCR-ABL construct, Motonari Kondo for providing Rag2 −/− IL2rγ −/− mice, Alan Chen and Yin Yiu for excellent technical help, Mike Cook and Beth Harvat for cell sorting, and Anthony Means, Brigid Hogan, and Terry Lechler for critical review of the manuscript. T.R. is a recipient of a Cancer Research Institute Investigator Award, an Ellison Medical Foundation New Scholar award, and a Leukemia and Lymphoma Society Scholar Award. This work was also supported by NIH grants DK63031 and DK072234 and a Duke Stem Cell Research Program grant to T.R.