Adipose tissue is central to the regulation of energy balance. Two functionally different types of fat are present in mammals: white adipose tissue (WAT), the primary site of triglyceride storage, and brown adipose tissue (BAT), which is specialized in energy expenditure and can counteract obesity1. Factors that specify the developmental fate and function of white and brown adipose tissue remain poorly understood2,3. Here, we demonstrate that while some members of the family of bone morphogenetic proteins (BMP) support white adipocyte differentiation, BMP-7 singularly promotes differentiation of brown preadipocytes even in the absence of the normally required hormonal induction cocktail. BMP-7 activates a full program of brown adipogenesis including induction of early regulators of brown fat fate PRDM164 and PGC-1 (PPARγ coactivator-1) α5, increased expression of brown fat defining marker uncoupling protein-1 (UCP-1) and adipogenic transcription factors peroxisome proliferator-activated receptor (PPAR)γ and CCAAT/enhancer-binding proteins (C/EBPs), and mitochondrial biogenesis via a p38 MAP kinase and PGC-1 dependent pathway. Moreover, BMP-7 triggers commitment of mesenchymal progenitor cells to a brown adipocyte lineage, and implantation of these cells into nude mice results in development of adipose tissue containing mostly brown adipocytes. BMP-7 knockout embryos show a marked paucity of brown fat and near complete absence of UCP-1 protein. Adenoviral-mediated expression of BMP-7 in mice results in a significant increase in brown, but not white, fat mass and leads to an increase in energy expenditure and reduced weight gain. These data reveal an important role of BMP-7 in promoting brown adipocyte differentiation and thermogenesis in vivo and in vitro, and provide a potential novel therapeutic approach for the treatment of obesity.

Proteins that are localized to the cell surface via glycosylphosphatidylinositol (gpi) anchors have been proposed to regulate cell signaling and cell adhesion events involved in tissue patterning. Conditional deletion of Piga, which encodes the catalytic subunit of an essential enzyme in the gpi-biosynthetic pathway, in the lateral plate mesoderm results in normally patterned limbs that display chondrodysplasia. Analysis of mutant and mosaic Piga cartilage revealed two independent cell autonomous defects. First, loss of Piga function interferes with signal reception by chondrocytes as evidenced by delayed maturation. Second, the proliferative chondrocytes, although present, fail to flatten and arrange into columns. We present evidence that the abnormal organization of mutant proliferative chondrocytes results from errors in cell intercalation. Collectively, our data suggest that the distinct morphological features of the proliferative chondrocytes result from a convergent extension-like process that is regulated independently of chondrocyte maturation.

SUMMARYFor tissues that develop throughout embryogenesis and into postnatal life, the generation of differentiated cells to promote tissue growth is at odds with the requirement to maintain the stem cell/progenitor cell population to preserve future growth potential. In the growth plate cartilage, this balance is achieved in part by establishing a proliferative phase that amplifies the number of progenitor cells prior to terminal differentiation into hypertrophic chondrocytes. Here, we show that endogenous calcium/calmodulin-dependent protein kinase II (CamkII, also known as Camk2) activity is upregulated prior to hypertrophy and that loss of CamkII function substantially blocks the transition from proliferation to hypertrophy. Wnt signaling and Pthrpinduced phosphatase activity negatively regulate CamkII activity. Release of this repression results in activation of multiple effector pathways, including Runx2-and -catenin-dependent pathways. We present an integrated model for the regulation of proliferation potential by CamkII activity that has important implications for studies of growth control and adult progenitor/stem cell populations.

The actin-associated protein Pdlim7 is essential for heart and fin development in zebrafish; however, the expression and function of this PDZ-LIM family member in the mammal has remained unclear. Here, we show that Pdlim7 predominantly localizes to actin-rich structures in mice including the heart, vascular smooth muscle, and platelets. To test the requirement for Pdlim7 in mammalian development and function, we analyzed a mouse strain with global genetic inactivation of Pdlim7. We demonstrate that Pdlim7 loss-of-function leads to significant postnatal mortality. Inactivation of Pdlim7 does not disrupt cardiac development, but causes mild cardiac dysfunction in adult mice. Adult Pdlim7 -/- mice displayed increased mitral and tricuspid valve annulus to body weight ratios. These structural aberrations in Pdlim7 -/- mice were supported by three-dimensional reconstructions of adult cardiac valves, which revealed increased surface area to volume ratios for the mitral and tricuspid valve leaflets. Unexpectedly, we found that loss of Pdlim7 triggers systemic venous and arterial thrombosis, leading to significant mortality shortly after birth in Pdlim7 +/- (11/60) and Pdlim7 -/- (19/35) mice. In line with a prothrombotic phenotype, adult Pdlim7 -/- mice exhibit dramatically decreased tail bleed times compared to controls. These findings reveal a novel and unexpected function for Pdlim7 in maintaining proper hemostasis in neonatal and adult mice.