Canonical notch signaling is dispensable for the maintenance of adult hematopoietic stem cells.
Gain-of-function experiments have demonstrated the potential of Notch signals to expand primitive hematopoietic progenitors, but whether Notch physiologically regulates hematopoietic stem cell (HSC) homeostasis in vivo is unclear. To answer this question, we evaluated the effect of global deficiencies of canonical Notch signaling in rigorous HSC assays. Hematopoietic progenitors expressing dominant-negative Mastermind-like1 (DNMAML), a potent inhibitor of Notch-mediated transcriptional activation, achieved stable long-term reconstitution of irradiated hosts and showed a normal frequency of progenitor fractions enriched for long-term HSCs. Similar results were observed with cells lacking CSL/RBPJ, a DNA-binding factor that is required for canonical Notch signaling. Notch-deprived progenitors provided normal long-term reconstitution after secondary competitive transplantation. Furthermore, Notch target genes were expressed at low levels in primitive hematopoietic progenitors. Taken together, these results rule out an essential physiological role for cell-autonomous canonical Notch signals in HSC maintenance.
Maillard
Ivan
I
Center for Stem Cell Biology, Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA.
Koch
Ute
U
Dumortier
Alexis
A
Shestova
Olga
O
Xu
Lanwei
L
Sai
Hong
H
Pross
Seth E
SE
Aster
Jon C
JC
Bhandoola
Avinash
A
Radtke
Freddy
F
Pear
Warren S
WS
D053687:Adult Stem Cells / Q000502:physiology*; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015139:Blotting, Southern; D001854:Bone Marrow Cells / Q000528:radiation effects; D002478:Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D005472:Fluorouracil / Q000494:pharmacology; D005799:Genes, Dominant / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000502:physiology*; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism; D019426:Integrases / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009124:Muscle Proteins / Q000378:metabolism; D022423:Myeloid Cells / Q000378:metabolism; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
D000964:Antimetabolites, Antineoplastic; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; C486455:Maml1 protein, mouse; D009124:Muscle Proteins; D009687:Nuclear Proteins; D012333:RNA, Messenger; D051880:Receptors, Notch; C499035:Smpx protein, mouse; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; C045073:Cre recombinase; D019426:Integrases; D005472:Fluorouracil