Extracellular matrix (ECM) is known to play several important roles in vascular development, although the molecular mechanisms behind these remain largely unknown. RECK, a tumor suppressor downregulated in a wide variety of cancers, encodes a membrane-anchored matrix-metalloproteinase-regulator. Mice lacking functional Reck die in utero, demonstrating its importance for mammalian embryogenesis; however, the underlying causes of mid-gestation lethality remain unclear. Using Reck conditional knockout mice, we have now demonstrated that the lack of Reck in vascular mural cells is largely responsible for mid-gestation lethality. Experiments using cultured aortic explants further revealed that Reck is essential for at least two events in sprouting angiogenesis; (1) correct association of mural and endothelial tip cells to the microvessels and (2) maintenance of fibronectin matrix surrounding the vessels. These findings demonstrate the importance of appropriate cell-cell interactions and ECM maintenance for angiogenesis and the involvement of Reck as a critical regulator of these events.

SummaryVirtually all diseases affect multiple organs. However, our knowledge of the body-wide effects remains limited. Here, we report the body-wide transcriptome landscape across 13–23 organs of mouse models of myocardial infarction, diabetes, kidney diseases, cancer, and pre-mature aging. Using such datasets, we find (1) differential gene expression in diverse organs across all models; (2) skin as a disease-sensor organ represented by disease-specific activities of putative gene-expression network; (3) a bone-skin cross talk mediated by a bone-derived hormone, FGF23, in response to dysregulated phosphate homeostasis, a known risk-factor for kidney diseases; (4) candidates for the signature activities of many more putative inter-organ cross talk for diseases; and (5) a cross-species map illustrating organ-to-organ and model-to-disease relationships between human and mouse. These findings demonstrate the usefulness and the potential of such body-wide datasets encompassing mouse models of diverse disease types as a resource in biological and medical sciences. Furthermore, the findings described herein could be exploited for designing disease diagnosis and treatment.

This research evaluated the monthly variation of plant mineral nutrition in six species of fruit trees over a year. Leaf samples were taken from the fruit trees and nutritional Cruz, A.F.; et al.

Approximately 90% of pre-clinically validated drugs fail in clinical trials owing to unanticipated clinical outcomes, costing over several hundred million US dollars per drug. Despite such critical importance, translating pre-clinical data to clinical outcomes remain a major challenge. Herein, we designed a modality-independent and unbiased approach to predict clinical outcomes of drugs. The approach exploits their multi-organ transcriptome patterns induced in mice and a unique mouse-transcriptome database ''humanized'' by machine learning algorithms and human clinical outcome datasets. The cross-validation with small-molecule, antibody, and peptide drugs shows effective and efficient identification of the previously known outcomes of 5,519 adverse events and 11,312 therapeutic indications. In addition, the approach is adaptable to deducing potential molecular mechanisms underlying these outcomes. Furthermore, the approach identifies previously unsuspected repositioning targets. These results, together with the fact that it requires no prior structural or mechanistic information of drugs, illustrate its versatile applications to drug development process.

Summary RECK in neural precursor cells (NPCs) was previously found to support Notch-dependent neurogenesis in mice. On the other hand, recent studies implicate RECK in endothelial cells (ECs) in WNT7-triggered canonical WNT signaling essential for brain angiogenesis. Here we report that RECK in NPCs is also critical for brain angiogenesis. When Reck is inactivated in Foxg1 -positive NPCs, mice die shortly after birth with hemorrhage in the forebrain, with angiogenic sprouts stalling at the periphery and forming abnormal aggregates reminiscent of those in EC-selective Reck knockout mice and Wnt7a/b -deficient mice. The hemorrhage can be pharmacologically suppressed by lithium chloride. An effect of RECK in WNT7-producing cells to enhance canonical WNT-signaling in reporter cells is detectable in mixed culture but not with conditioned medium. Our findings suggest that NPC-expressed RECK has a non-cell-autonomous function to promote forebrain angiogenesis through contact-dependent enhancement of WNT signaling in ECs, implying possible involvement of RECK in neurovascular coupling.