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i Mammalian DREAM is a conserved protein complex that functions in cellular quiescence. DREAM contains an E2F, a retinoblastoma (RB)-family protein, and the MuvB core (LIN9, LIN37, LIN52, LIN54, and RBBP4). In mammals, MuvB can alternatively bind to BMYB to form a complex that promotes mitotic gene expression. Because BMYB-MuvB is essential for proliferation, loss-of-function approaches to study MuvB have generated limited insight into DREAM function. Here, we report a gene-targeted mouse model that is uniquely deficient for DREAM complex assembly. We have targeted p107 (Rbl1) to prevent MuvB binding and combined it with deficiency for p130 (Rbl2). Our data demonstrate that cells from these mice preferentially assemble BMYB-MuvB complexes and fail to repress transcription. DREAM-deficient mice show defects in endochondral bone formation and die shortly after birth. Micro-computed tomography and histology demonstrate that in the absence of DREAM, chondrocytes fail to arrest proliferation. Since DREAM requires DYRK1A (dual-specificity tyrosine phosphorylation-regulated protein kinase 1A) phosphorylation of LIN52 for assembly, we utilized an embryonic bone culture system and pharmacologic inhibition of (DYRK) kinase to demonstrate a similar defect in endochondral bone growth. This reveals that assembly of mammalian DREAM is required to induce cell cycle exit in chondrocytes.C ellular differentiation is generally controlled by transcriptional activation or repression of specific genes. Consequently, a host of different molecular genetic events can shape the properties of cells during development. Recent evidence indicates that an evolutionarily conserved protein complex known as DREAM is capable of regulating diverse gene expression programs, thereby unifying many disparate events in development into a single molecular machine (1, 2).The DREAM complex was isolated, and its composition was determined from a number of different model organisms. Studies of aberrant growth factor signaling in Caenorhabditis elegans lead to the discovery of complementation groups that contribute to a multivulval (Muv) phenotype (3). Mutation of any two of the synthetic multivulval (synMuv) group A, B, or C genes resulted in worms with elevated numbers of vulvae (4). Group B contains a number of genes (the Lin-9, Lin-37, Lin-52, Lin-53/RBBP4, and Lin-54 genes) whose encoded proteins form the MuvB core complex (5-7). In addition, worm homologues of retinoblastoma protein (RB), E2F, and DP are also group B members (8, 9). The MuvB core was also found to interact with MYB in transcriptional control of cell cycle progression in fruit flies (6, 7). Isolation of MYB and RB revealed that they copurify with MuvB proteins, and this has formed the basis of the DREAM complex (Drosophila RB, E2F, and MuvB). In some organisms it also contains epigenetic readers and writers such as histone deacetylases (HDACs) and L3MBT (6,7,10). The model that has emerged is one in which the DREAM complex can confer both positive and negative regulation of transcripti...

Glycogen synthase kinase 3 β (GSK-3β) is an essential negative regulator or "brake" on many anabolic-signaling pathways including Wnt and insulin. Global deletion of GSK-3β results in perinatal lethality and various skeletal defects. The goal of our research was to determine GSK-3β cell-autonomous effects and postnatal roles in the skeleton. We used the 3.6-kb Col1a1 promoter to inactivate the Gsk3b gene (Col1a1-Gsk3b knockout) in skeletal cells. Mutant mice exhibit decreased body fat and postnatal bone growth, as well as delayed development of several skeletal elements. Surprisingly, the mutant mice display decreased circulating glucose and insulin levels despite normal expression of GSK-3β in metabolic tissues. We showed that these effects are due to an increase in global insulin sensitivity. Most of the male mutant mice died after weaning. Prior to death, blood glucose changed from low to high, suggesting a possible switch from insulin sensitivity to resistance. These male mice die with extremely large bladders that are preceded by damage to the urogenital tract, defects that are also seen type 2 diabetes. Our data suggest that skeletal-specific deletion of GSK-3β affects global metabolism and sensitizes male mice to developing type 2 diabetes.