Abstract
Notch signaling between neighboring cells controls many cell fate decisions in metazoans both during embryogenesis and in postnatal life. Previously, we uncovered a critical role for physiological Notch signaling in suppressing osteoblast differentiation in vivo. However, the contribution of individual Notch receptors and the downstream signaling mechanism have not been elucidated. Here we report that removal of Notch2, but not Notch1, from the embryonic limb mesenchyme markedly increased trabecular bone mass in adolescent mice. Deletion of the transcription factor RBPjk, a mediator of all canonical Notch signaling, in the mesenchymal progenitors but not the more mature osteoblast-lineage cells, caused a dramatic high-bone-mass phenotype characterized by increased osteoblast numbers, diminished bone marrow mesenchymal progenitor pool, and rapid age-dependent bone loss. Moreover, mice deficient in Hey1 and HeyL, two target genes of Notch-RBPjk signaling, exhibited high bone mass. Interestingly, Hey1 bound to and suppressed the NFATc1 promoter, and RBPjk deletion increased NFATc1 expression in bone. Finally, pharmacological inhibition of NFAT alleviated the high-bone-mass phenotype caused by RBPjk deletion. Thus, Notch-RBPjk signaling functions in part through Hey1-mediated inhibition of NFATc1 to suppress osteoblastogenesis, contributing to bone homeostasis in vivo.
Highlights
Notch signaling mediates communication between neighboring cells to control cell fate decisions in all metazoans [1,2]
More recent mouse genetic studies have expanded our view of Notch function in the osteoblast lineage. By genetically removing both catalytic subunits of the c-secretase complex, presenilin 1 (PS1) and PS2, or both Notch1 and 2 in the embryonic limb mesenchyme, we have shown that Notch critically controls postnatal bone homeostasis: the Notch-deficient long bones exhibited excessive bone formation in adolescent mice with concomitant loss of bone marrow mesenchymal progenitors [21]
Simultaneous removal of both Notch1 and 2 (PNN mice) from the embryonic limb mesenchyme with Prx1-Cre, which targets all of the early limb bud mesenchyme and a subset of the craniofacial mesenchyme [34], caused high bone mass due to increased osteoblast differentiation [21]
Summary
Notch signaling mediates communication between neighboring cells to control cell fate decisions in all metazoans [1,2]. In the canonical Notch pathway, binding of the ligands to the Notch receptors present on the neighboring cell surface triggers two successive intramembrane proteolytic cleavages of the receptors mediated by the c-secretase complex and resulting in the release of the Notch intracellular domain (NICD) [4,5,6]. Upon its release from the plasma membrane, NICD translocates to the nucleus where it interacts with a transcription factor of the CSL family (RBPjk/CBF-1 in mammals) to activate transcription of target genes [7]. Among the best known targets of Notch/RBPjk signaling are the Hes/Hey family of basic helix-loop-helix (bHLH) transcription repressors [8]. The regulation of individual Hes/Hey proteins by Notch and their role in mediating Notch function are highly dependent on cell context. In addition to the canonical pathway, Notch has been reported to signal through noncanonical, RBPjk-independent mechanisms, but the molecular nature of these mechanisms is not well understood [6,9,10,11]
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