SUMMARY The vertebrate limb is a classical model for understanding patterning of three-dimensional structures during embryonic development. While decades of research have elucidated the tissue and molecular interactions within the limb bud required for patterning and morphogenesis of the limb, the cellular and molecular events that shape the limb bud itself have remained largely unknown. We show that the mesenchymal cells of the early limb bud are not disorganized within the ectoderm as previously thought, but instead are highly organized and polarized. Using time lapse video microscopy we demonstrate that cells move and divide according to this orientation. The combination of oriented cell divisions and movements drives the proximal-to-distal elongation of the limb bud necessary to set the stage for subsequent patterning and morphogenesis. These cellular events are regulated by the combined activities of the Wnt and FGF pathways. We show that Wnt5a/JNK is necessary for the proper orientation of cell movements and cell division. In contrast FGF/Mapk signalling pathway, emanating from the AER, does not regulate cell orientation in the limb bud but instead establishes a gradient of cell velocity enabling continuous rearrangement of the cells at the distal tip of limb.
Fusion imaging of radionuclide-based molecular (PET) and structural data [x-ray computed tomography (CT)] has been firmly established. Here we show that optical measurements [fluorescence-mediated tomography (FMT)] show exquisite congruence to radionuclide measurements and that information can be seamlessly integrated and visualized. Using biocompatible nanoparticles as a generic platform (containing a 18 F isotope and a far red fluorochrome), we show good correlations between FMT and PET in probe concentration (r 2 > 0.99) and spatial signal distribution (r 2 > 0.85). Using a mouse model of cancer and different imaging probes to measure tumoral proteases, macrophage content and integrin expression simultaneously, we demonstrate the distinct tumoral locations of probes in multiple channels in vivo. The findings also suggest that FMT can serve as a surrogate modality for the screening and development of radionuclide-based imaging agents.fluorescence-mediated tomography | molecular imaging | multimodal image fusion | computed tomography T oday, clinical imaging is used largely to provide anatomic, physiological, and metabolic information, but it generally cannot provide information about the underlying molecular aberrations of disease. Molecular imaging probes have the potential to provide such information by interrogating specific targets, such as cell surface receptors, enzymes, and structural proteins. By detecting specific molecular markers, imaging probes could vastly improve the early detection and staging of disease, and thus promote tailoring of targeted therapies for individual patients. There is also considerable interest in identifying and validating surrogate imaging biomarkers as indicators of drug efficacy in clinical trials and medical practice (1).Increasingly, particular attention has been paid to the development of combined PET-optical molecular imaging agents for translational applications, because these two modalities can provide complementary molecular information. A combined approach would be invaluable for purposes such as whole-body imaging (with, e.g., PET) and subsequent surgical intervention (with, e.g., an intraoperative optical imaging system). Moreover, because preclinical studies can use optical modalities, a combined approach would significantly reduce the hurdles commonly encountered with nuclear imaging and thus accelerate throughput and the development of PET imaging agents. For instance, this strategy would obviate some of the need for expensive equipment, controlled facilities, and a local cyclotron for supplying the radionuclide, and also would reduce the costs associated with handling radioactivity. Furthermore, by targeting the agent toward a surrogate biomarker, its specific localization within the tissue could be visualized via fluorescence; thus, this technique could provide a better understanding of underlying pathophysiology of disease.A unique platform for the combined development of targeted multifunctional imaging agents is provided by biocompatible nanoparticles (2-...
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