The expansion of GPCR transactivation-dependent signalling to include serine/threonine kinase receptors represents a new cell signalling frontier

G protein-coupled receptor (GPCR) signalling is mediated through transactivation-independent signalling pathways or the transactivation of protein tyrosine kinase receptors and the recently reported activation of the serine/threonine kinase receptors, most notably the transforming growth factor-β receptor family. Since the original observation of GPCR transactivation of protein tyrosine kinase receptors, there has been considerable work on the mechanism of transactivation and several pathways are prominent. These pathways include the “triple membrane bypass” pathway and the generation of reactive oxygen species. The recent recognition of GPCR transactivation of serine/threonine kinase receptors enormously broadens the GPCR signalling paradigm. It may be predicted that the transactivation of serine/threonine kinase receptors would have mechanistic similarities with transactivation of tyrosine kinase pathways; however, initial studies suggest that these two transactivation pathways are mechanistically distinct. Important questions are the relative importance of tyrosine and serine/threonine transactivation pathways, the contribution of transactivation to overall GPCR signalling, mechanisms of transactivation and the range of cell types in which this phenomenon occurs. The ultimate significance of transactivation-dependent signalling remains to be defined but it appears to be prominent and if so will represent a new cell signalling frontier.     

Induction of hemopoietic chimerism in the caprine fetus by intraperitoneal injection of fetal liver cells

Summary Intraperitoneal injection of allogeneic liver cells from 43-day-old male fetuses into normal 60-day female goat fetuses resulted in persistent hemopoietic chimerism in surviving recipients without clinical evidence of graft-versus-host disease. Transplantation of normal fetal liver cells into preimmunocompetent goat fetuses affected with -D-mannosidosis may provide an alternative strategy for evaluating hemopoietic stem cell transplantation in the treatment of human lysosomal storage diseases.     

Mate sampling in a natural population of Pecos gambusia, Gambusia nobilis

Normal 0 false false false MicrosoftInternetExplorer4 st1\:*{behavior:url(#ieooui) } /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman"; mso-ansi-language:#0400; mso-fareast-language:#0400; mso-bidi-language:#0400;} Much research has been conducted on the mating systems of poeciliid fish in aquaria; however, there are fewer studies that examine mate sampling of these fish in the wild. In general, male poeciliids are characterized as being unselective in their mate choices and will attempt to copulate with seemingly all available females. Females are selective, copulate infrequently, and are often pursued by “ardent” males who may force copulations. To avoid male harassment, females in aquaria will often shelter from males among other females in shoals. Here, we examined the mate-sampling behaviors of male and female Pecos gambusia Gambusia nobilis by following individuals swimming in an outflow pool of Diamond Y Spring in southwestern Texas. In most cases, a male approached a solitary female, followed her briefly, and then left for no apparent reason. Approaching a number of females increased the likelihood that the male would follow one, and the longer a male followed a female, the more likely he was to copulate with her. As females were larger and faster than males, they could avoid males by swimming away from them. We found no evidence of the persistent males that harass seemingly unreceptive females as seen under aquarium conditions, nor did we see females join a shoal to stop pursuit by males. However, the activity of one male following a female did appear to attract other males who would compete to follow and attempt copulation. This competition might ensure that only superior males gain reproductive opportunities. Se han investigado extensamente los sistemas de apareamiento de pecílidos en acuario; no obstante, hay relativamente pocos estudios que examinan la elección de pareja de estos peces en su hábitat natural. Los pecílidos machos no suelen ser selectivos en su elección de pareja y parecen intentar copular con todas las hembras que estén a su alcance. Las hembras son selectivas, no copulan frecuentemente y a menudo las persiguen machos excitados que pueden copular con ellas forzadamente. Para evitar el acosamiento de los machos, en acuario las hembras a menudo se refugian de los machos entre otras hembras en bancos. Para este estudio, examinamos el comportamiento de elección de pareja de gambusias de pecos ( Gambusia nobilis ) machos y hembras al observar algunos individuos en un remanso del Diamond Y Spring en el suroeste de Texas. En la mayoría de los casos, el macho se acercaba a una hembra solitaria, la seguía brevemente y luego se alejaba sin motivo aparente. El acercarse a varias hembras aumentaba la probabilidad de que persiguiera a una de ellas, y cuanto más la seguía, más probable era que copulara con ella. Dado que las hembras son más grandes y más rápidas que los machos, podían eludirlos si no correspondían. No observamos machos persistentes que acosaran hembras aparentemente poco receptivas como se ha documentado en acuario, ni tampoco vimos hembras que se unieran a bancos para evitar la persecución de machos. Pero cuando un macho perseguía una hembra, parecía atraer otros, los cuales competían entre sí para seguirla e intentar copular con ella. Esta competencia podría garantizar que solo los machos superiores tengan oportunidades reproductivas.     

Rescue of embryonic lethality in Mdm4-null mice by loss of Trp53 suggests a nonoverlapping pathway with MDM2 to regulate p53

The relationship between the neurosensory photoreceptors and the adjacent retinal pigment epithelium (RPE) controls not only normal retinal function, but also the pathogenesis of hereditary retinal degenerations. The molecular bases for both primary photoreceptor and RPE diseases that cause blindness have been identified. Gene therapy has been used successfully to slow degeneration in rodent models of primary photoreceptor diseases, but efficacy of gene therapy directed at photoreceptors and RPE in a large-animal model of human disease has not been reported. Here we study one of the most clinically severe retinal degenerations, Leber congenital amaurosis (LCA). LCA causes near total blindness in infancy and can result from mutations in RPE65 (LCA, type II; MIM 180069 and 204100). A naturally occurring animal model, the RPE65-/- dog, suffers from early and severe visual impairment similar to that seen in human LCA. We used a recombinant adeno-associated virus (AAV) carrying wild-type RPE65 (AAV-RPE65) to test the efficacy of gene therapy in this model. Our results indicate that visual function was restored in this large animal model of childhood blindness.