Retinoic acid receptor antagonism in vivo expands the numbers of precursor cells during granulopoiesis.
The role/s of retinoids in granulopoiesis has been recognised for many years, being powerful differentiation inducers. The physiological role/s of retinoic acid receptor (RAR)-mediated signalling during adult haemopoiesis has by contrast proved more elusive. The recent generation of highly specific pan-RAR antagonists has now made possible an assessment of the specific physiological role/s of RAR signalling, allowing the separation for the first time of the RAR and RXR pathways. Mice were treated with AGN194310, a synthetic retinoid that antagonises the physiological function of the three RAR isotypes (alpha, beta, gamma) but does not interact with RXRs. Analyses of the granulocytic lineage using Gr-1, c-Kit and CD11b antibodies, demonstrated that granulocyte numbers were strikingly increased across haemopoietic compartments in all AGN194310-treated mice. A significant increase in the frequency of progenitor cells containing granulocytes was observed in the bone marrow of mice following treatment with AGN194310. In contrast we were not able to detect any differences in cell death of either mature granulocytes or granulocytic progenitors from AGN194310-treated mice compared with control animals. These data demonstrate an essential role for RAR signalling in regulating the numbers of granulocytic precursors in vivo.
Molecular Oncology Laboratory, Peter MacCallum Cancer Institute, East Melbourne, Australia.
C R
CR
Walkley
Y-D
YD
Yuan
R A S
RA
Chandraratna
G A
GA
McArthur
D000818:Animals; D001565:Benzoates / Q000008:administration & dosage / Q000494:pharmacology; D001854:Bone Marrow Cells / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002460:Cell Line; D003114:Colony-Forming Units Assay; D005260:Female; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects / Q000378:metabolism*; D006410:Hematopoiesis / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018168:Receptors, Retinoic Acid / Q000037:antagonists & inhibitors / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*; D013876:Thiophenes / Q000008:administration & dosage / Q000494:pharmacology
C121616:4-((4-(4-ethylphenyl)-2,2-dimethyl-(2H)-thiochromen-6-yl)ethynyl)benzoic acid; D001565:Benzoates; D018168:Receptors, Retinoic Acid; D013876:Thiophenes