Cdo patterns the musculature of the esophagus and is required for esophageal motility in mice

Introduction: Cdo is a multifunctional cell surface co-receptor that promotes Hedgehog signaling during rostroventral midline development and cadherin-mediated signaling during skeletal myogenesis. We report here novel roles for Cdo in patterning of the murine esophageal musculature and esophageal motility disorders such as achalasia

Positive Regulation of Myogenic bHLH Factors and Skeletal Muscle Development by the Cell Surface Receptor CDO

AbstractSkeletal myogenesis is controlled by bHLH transcription factors of the MyoD family that, along with MEF-2 factors, comprise a positive feedback network that maintains the myogenic transcriptional program. Cell-cell contact between muscle precursors promotes myogenesis, but little is known of the underlying mechanisms. CDO, an Ig superfamily member, is a component of a cell surface receptor complex found at sites of cell-cell contact that positively regulates myogenesis in vitro. We report here that mice lacking CDO display delayed skeletal muscle development. Additionally, satellite cells from these mice differentiate defectively in vitro. CDO functions to activate myogenic bHLH factors via enhanced heterodimer formation, most likely by inducing hyperphosphorylation of E proteins. The Cdo gene is, in turn, a target of MyoD. The promyogenic effect of cell-cell contact is therefore linked to the activity of myogenic bHLH factors. Furthermore, the myogenic positive feedback network extends from the cell surface to the nucleus

Regulation of myotube formation by the actin-binding factor drebrin

<p>Abstract</p> <p>Background</p> <p>Myogenic differentiation involves cell-cycle arrest, activation of the muscle-specific transcriptome, and elongation, alignment and fusion of myoblasts into multinucleated myotubes. This process is controlled by promyogenic transcription factors and regulated by signaling pathways in response to extracellular cues. The p38 mitogen-activated protein kinase (p38 MAPK) pathway promotes the activity of several such transcription factors, including MyoD and MEF2, thereby controlling the muscle-specific transcription program. However, few p38-regulated genes that play a role in the regulation of myogenesis have been identified.</p> <p>Methods</p> <p>RNA interference (RNAi), chemical inhibition and immunofluorescence approaches were used to assess the role of drebrin in differentiation of primary mouse myoblasts and C2C12 cells.</p> <p>Results</p> <p>In a search for p38-regulated genes that promote myogenic differentiation, we identified <it>Dbn1</it>, which encodes the actin-binding protein drebrin. Drebrin is an F-actin side-binding protein that remodels actin to facilitate the change of filopodia into dendritic spines during synaptogenesis in developing neurons. <it>Dbn1 </it>mRNA and protein are induced during differentiation of primary mouse and C2C12 myoblasts, and induction is substantially reduced by the p38 MAPK inhibitor SB203580. Primary myoblasts and C2C12 cells depleted of drebrin by RNAi display reduced levels of myogenin and myosin heavy chain and form multinucleated myotubes very inefficiently. Treatment of myoblasts with BTP2, a small-molecule inhibitor of drebrin, produces a phenotype similar to that produced by knockdown of drebrin, and the inhibitory effects of BTP2 are rescued by expression of a mutant form of drebrin that is unable to bind BTP2. Drebrin in myoblasts is enriched in cellular projections and cell cortices and at regions of cell-cell contact, all sites where F-actin, too, was concentrated.</p> <p>Conclusions</p> <p>Our findings reveal that <it>Dbn1 </it>expression is a target of p38 MAPK signaling during myogenesis and that drebrin promotes myoblast differentiation.</p

The Cell Surface Membrane Proteins Cdo and Boc Are Components and Targets of the Hedgehog Signaling Pathway and Feedback Network in Mice

SummaryCdo and Boc encode cell surface Ig/fibronectin superfamily members linked to muscle differentiation. Data here indicate they are also targets and signaling components of the Sonic hedgehog (Shh) pathway. Although Cdo and Boc are generally negatively regulated by Hedgehog (HH) signaling, in the neural tube Cdo is expressed within the Shh-dependent floor plate while Boc expression lies within the dorsal limit of Shh signaling. Loss of Cdo results in a Shh dosage-dependent reduction of the floor plate. In contrast, ectopic expression of Boc or Cdo results in a Shh-dependent, cell autonomous promotion of ventral cell fates and a non-cell-autonomous ventral expansion of dorsal cell identities consistent with Shh sequestration. Cdo and Boc bind Shh through a high-affinity interaction with a specific fibronectin repeat that is essential for activity. We propose a model where Cdo and Boc enhance Shh signaling within its target field

The Uncertainty in Newton's Constant and Precision Predictions of the Primordial Helium Abundance

The current uncertainty in Newton's constant, G_N, is of the order of 0.15%. For values of the baryon to photon ratio consistent with both cosmic microwave background observations and the primordial deuterium abundance, this uncertainty in G_N corresponds to an uncertainty in the primordial 4He mass fraction, Y_P, of +-1.3 x 10^{-4}. This uncertainty in Y_P is comparable to the effect from the current uncertainty in the neutron lifetime, which is often treated as the dominant uncertainty in calculations of Y_P. Recent measurements of G_N seem to be converging within a smaller range; a reduction in the estimated error on G_N by a factor of 10 would essentially eliminate it as a source of uncertainty in the calculation of the primordial 4He abundance.Comment: 3 pages, no figures, fixed typos, to appear in Phys. Rev.