Stage-specific functions of leukemia/lymphoma-related factor (LRF) in the transcriptional control of osteoclast development.
Cell fate determination is tightly regulated by transcriptional activators and repressors. Leukemia/lymphoma-related factor (LRF; encoded by Zbtb7a), known as a POK (POZ/BTB and Krüppel) family transcriptional repressor, is induced during the development of bone-resorbing osteoclasts, but the physiological significance of LRF in bone metabolism and the molecular mechanisms underlying the transcriptional regulation of osteoclastogenesis by LRF have not been elucidated. Here we show that LRF negatively regulates osteoclast differentiation by repressing nuclear factor of activated T cells c1 (NFATc1) induction in the early phase of osteoclast development, while positively regulating osteoclast-specific genes by functioning as a coactivator of NFATc1 in the bone resorption phase. The stage-specific distinct functions of LRF were demonstrated in two lines of conditional knockout mice in which LRF was deleted in the early or late phase of osteoclast development. Thus, this study shows that LRF plays stage-specific distinct roles in osteoclast differentiation, exemplifying the delicate transcriptional regulation at work in lineage commitment.
Department of Cell Signaling, Graduate School of Medical and Dental Sciences,  Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8549,  Japan.
Kaori
K
Tsuji-Takechi
Takako
T
Negishi-Koga
Eriko
E
Sumiya
Akiko
A
Kukita
Shigeaki
S
Kato
Takahiro
T
Maeda
Pier Paolo
PP
Pandolfi
Keiji
K
Moriyama
Hiroshi
H
Takayanagi
D000818:Animals; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D051379:Mice; D010010:Osteoclasts / Q000166:cytology*; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
D004268:DNA-Binding Proteins; D014157:Transcription Factors; C485514:ZBTB7A protein, human