This Week in PNAS
DEVELOPMENTAL BIOLOGY
Bmpr1a and Bmpr1b essential for cartilage formation
Byeong Yoon et al. report that bone morphogenetic protein (BMP) signaling is essential for the generation of chondrocytes in vivo. During development, chondrocytes proliferate and form the cartilage that acts as the template for bone formation. Previous studies have demonstrated that BMPs can promote differentiation of chondrocytes in vitro. To clarify the in vivo role of BMP signaling during chondrocyte development, Yoon et al. generated mice lacking the BMP receptors Bmpr1a and Bmpr1b in chondrocytes. The researchers showed that mice deficient in either Bmpr1a or Bmpr1b were able to form cartilage elements and had few skeletal defects, but Bmpr1a/Bmpr1b double mutants developed severe generalized chondrodysplasia, including delayed bone formation and shortened long bones. Cartilage condensations in double mutants were reduced in size because of decreased proliferation and increased apoptosis. The few cartilage condensations that developed were arrested in the prechondrocytic stage and never formed an organized growth plate. In addition, the mutant cartilage lacked Sox9, a transcription factor involved in early chondrocyte differentiation, as well as the downstream targets of Sox9, L-Sox5, and Sox6. The authors conclude that Bmpr1a and Bmpr1b are functionally redundant during early chondrogenesis and that BMP signaling is required for chondrocyte proliferation, survival, and differentiation in vivo.
Bmpr1a and Bmpr1b required for chondrogenesis.
“Bmpr1a and Bmpr1b have overlapping functions and are essential for chondrogenesis in vivo” by Byeong S. Yoon, Dmitry A. Ovchinnikov, Isaac Yoshii, Yuji Mishina, Richard R. Behringer, and Karen M. Lyons (see pages 5062–5067)
DEVELOPMENTAL BIOLOGY
Transcription factors control snapdragon asymmetry
RAD, a transcription factor expressed in the dorsal region of a developing snapdragon (Antirrhinum majus), helps coordinate the genes that control the flower's unique asymmetrical shape, according to Susie Corley et al. Four transcription factors, CYC, DICH, DIV, and RAD, determine the formation of dorsoventral asymmetry in the snapdragon, but how they interact is unclear. Corley et al. cloned RAD and looked for its expression in the developing flowers of both wild-type and mutant plants. The authors found that RAD encodes a small protein with a MYB-like domain and is thus a member of one of the largest transcription factor families in plants. RAD was activated in the dorsal region of developing flowers by CYC and DICH, and, once activated, RAD antagonized DIV, preventing its activity in the dorsal regions. DIV produces a transcription factor that leads to petals with ventral characteristics. RAD transcription factor is similar in sequence to the N-terminal domain of DIV, also a MYB transcription factor. This similarity suggests that the two transcription factors compete for binding sites on DNA or interacting proteins. The authors suggest that RAD evolved from DIV or a common precursor via C-terminal deletion.
Genetic control of snapdragon asymmetry.
“Floral asymmetry involves an interplay between TCP and MYB transcription factors in Antirrhinum” by Susie B. Corley, Rosemary Carpenter, Lucy Copsey, and Enrico Coen (see pages 5068–5073)
IMMUNOLOGY
Neuronal receptor VR1 involved in immune cell function
Sreyashi Basu and Pramod Srivastava report that capsaicin, the spicy component of chili peppers, induces maturation in dendritic cells (DCs), key antigen-presenting cells of the immune system. In the nervous system, capsaicin and thermal heat work in a similar manner by activating the vanilloid receptor 1 (VR1) receptor on sensory neurons, explaining why capsaicin elicits a burning sensation. In a previous study, Basu and Srivastava observed that heat stimulates DCs to mature, and they hypothesized that these immune cells also detect heat via the VR1 receptor pathway. In the current study, the researchers demonstrate that immature DCs in mice express the VR1 receptor. When the immature DCs were treated with capsaicin to activate VR1, the DCs matured, as measured by up-regulation of antigen-presenting molecules. To test the functionality of VR1, the researchers exposed DCs from VR1+/+ and VR1–/– mice to either capsaicin or heat (41°C). DCs from VR1+/+ mice matured when exposed to heat or capsaicin, whereas DCs from VR1–/– mice matured in response to heat alone. Furthermore, injection of capsaicin into the skin caused DCs to migrate to draining lymph nodes in VR1+/+ mice but not VR1–/– mice. These data indicate that VR1 is not responsible for heat-induced maturation of DCs, but that capsaicin affects DC activity via VR1, demonstrating a common mechanistic pathway between neural and immune functions.
Mouse dendritic cells, stained with antibodies to VR1 (red).
“Immunological role of neuronal receptor vanilloid receptor 1 expressed on dendritic cells” by Sreyashi Basu and Pramod Srivastava (see pages 5120–5125)
MEDICAL SCIENCES
Leptin's role in multiple sclerosis
According to Giuseppe Matarese et al., increased levels of the cytokine-like hormone leptin in individuals with multiple sclerosis (MS) inversely correlates with the frequency of CD4+CD25+ regulatory T cells (TRegs). Previous research has shown that leptin plays a significant role in the pathogenesis of autoimmune diseases such as experimental autoimmune encephalomyelitis, an animal model for MS. The role of leptin in the pathogenesis of human MS is not fully understood. The authors studied 126 naïve-to-therapy, relapsing–remitting MS patients and detected an increase in leptin in both their cerebrospinal fluid and serum. This increase correlated with elevated IFN-γ levels. Matarese et al. generated T cell lines from three of the individuals and, after activating the cells with human myelin basic protein, found an increase in leptin production and up-regulation of the leptin receptor. Anti-leptin or an anti-leptin-receptor blocking antibody inhibited the proliferative response of these T cells by up to 60%. Immunophenotypic analysis of peripheral blood from the MS patients showed a significant reduction in percentage and absolute number of TRegs, whereas no difference was observed in the frequency of other cell subpopulations. Treatment of experimental autoimmune encephalomyelitis mice with leptin antagonists increased the percentage of TRegs and slowed disease progression.
Anti-leptin inhibits T cell proliferation in MS.
“Leptin increase in multiple sclerosis associates with reduced number of CD4 + CD25 + regulatory T cells” by Giuseppe Matarese, Pietro Biagio Carrieri, Antonio La Cava, Francesco Perna, Veronica Sanna, Veronica De Rosa, Daniela Aufiero, Silvia Fontana, and Serafino Zappacosta (see pages 5150–5155)
