Clearance of fibrin through proteolytic degradation is a critical step of matrix remodeling that contributes to tissue repair in a variety of pathological conditions, such as stroke, atherosclerosis, and pulmonary disease. However, the molecular mechanisms that regulate fibrin deposition are not known. Here, we report that the p75 neurotrophin receptor (p75NTR), a TNF receptor superfamily member up-regulated after tissue injury, blocks fibrinolysis by down-regulating the serine protease, tissue plasminogen activator (tPA), and up-regulating plasminogen activator inhibitor-1 (PAI-1). We have discovered a new mechanism in which phosphodiesterase PDE4A4/5 interacts with p75NTR to enhance cAMP degradation. The p75NTR-dependent down-regulation of cAMP results in a decrease in extracellular proteolytic activity. This mechanism is supported in vivo in p75NTR-deficient mice, which show increased proteolysis after sciatic nerve injury and lung fibrosis. Our results reveal a novel pathogenic mechanism by which p75NTR regulates degradation of cAMP and perpetuates scar formation after injury.
Crayfish rely on the chemosensory neurons in their antennules to help them find food and habitat and to mediate social interactions. These structures often sustain damage from aggressive interactions or from the environment, but they have the ability to regenerate. In this study, we examine whether the effects of antennule ablation and regeneration on odor-tracking ability correlate with structural changes in the antennule that occur during regeneration. We initiated the regeneration process by removing the right antennules from 55 individuals of Orconectes sanborni. We developed a method to nondestructively sample the regenerating antennules so that we could follow the growth of new antennular tissue in the same animals over time. We used dental epoxy to make molds of the regenerating antennule after each molt. We then made resin positives, which were visualized using scanning electron microscopy. Structural parameters including aesthetasc length, diameter, segment length, and number per row were measured from scanning electron micrographs using Image J software. Crayfish were tested in a tabletop water Y-maze before and after surgery and after each molt to assess their ability to track food odors. The structural and the behavioral data indicate that the antennules possessed many aspects of their original structure by the end of the second molt. Flicking of antennules, investigation of substrate, success rate at finding the odor-containing Y-maze branch, and time to completion of Y-maze regained pre-antennulectomy values by the end of the third molt.
The transition of Drosophila third instar larvae from feeding, photo-phobic foragers to non-feeding, photo-neutral wanderers is a classic behavioral switch that precedes pupariation. The neuronal network responsible for this behavior has recently begun to be defined. Previous genetic analyses have identified signaling components for food and light sensory inputs and neuropeptide hormonal outputs as being critical for the forager to wanderer transition. Trio is a Rho-Guanine Nucleotide Exchange Factor integrated into a variety of signaling networks including those governing axon pathfinding in early development. Sequoia is a pan-neuronally expressed zinc-finger transcription factor that governs dendrite and axon outgrowth. Using pre-pupal lethality as an endpoint, we have screened for dominant second-site enhancers of a weakly lethal trio mutant background. In these screens, an allele of sequoia has been identified. While these mutants have no obvious disruption of embryonic central nervous system architecture and survive to third instar larvae similar to controls, they retain forager behavior and thus fail to pupariate at high frequency.
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