Reduced mechanical stress leads to bone loss, as evidenced by disuse osteoporosis in bedridden patients and astronauts. Osteocytes have been identified as major cells responsible for mechanotransduction; however, the mechanism underlying the response of bone to mechanical unloading remains poorly understood. In this study, we found that mechanical unloading of wildtype mice caused decrease of Wnt/b-catenin signaling activity accompanied by upregulation of Sost. To further analyze the causal relationship among these events, Sost gene targeting mice were generated. We showed that sclerostin selectively inhibited Wnt/ b-catenin in vivo, and sclerostin suppressed the activity of osteoblast and viability of osteoblasts and osteocytes. Interestingly, Sost 2/2 mice were resistant to mechanical unloading-induced bone loss. Reduction in bone formation in response to unloading was also abrogated in the mutant mice. Moreover, in contrast to wildtype mice, Wnt/b-catenin signaling was not altered by unloading in Sost 2/2 mice. Those data implied that sclerostin played an essential role in mediating bone response to mechanical unloading, likely through Wnt/ b-catenin signaling. Our findings also indicated sclerostin is a promising target for preventing disuse osteoporosis.

Pulmonary neuroendocrine cells (PNECs) are proposed to be the first specialized cell type to appear in the lung, but their ontogeny remains obscure. Although studies of PNECs have suggested their involvement in a number of lung functions, neither their in vivo significance nor the molecular mechanisms underlying them have been elucidated. Importantly, PNECs have long been speculated to constitute the cells of origin of human small-cell lung cancer (SCLC) and recent mouse models support this hypothesis. However, a genetic system that permits tracing the early events of PNEC transformation has not been available. To address these key issues, we developed a genetic tool in mice by introducing a fusion protein of Cre recombinase and estrogen receptor (CreER) into the calcitonin gene-related peptide (CGRP) locus that encodes a major peptide in PNECs. The CGRP CreER mouse line has enabled us to manipulate gene activity in PNECs. Lineage tracing using this tool revealed the plasticity of PNECs. PNECs can be colabeled with alveolar cells during lung development, and following lung injury, PNECs can contribute to Clara cells and ciliated cells. Contrary to the current model, we observed that elimination of PNECs has no apparent consequence on Clara cell recovery. We also created mouse models of SCLC in which CGRP CreER was used to ablate multiple tumor suppressors in PNECs that were simultaneously labeled for following their fate. Our findings suggest that SCLC can originate from differentiated PNECs. Together, these studies provide unique insight into PNEC lineage and function and establish the foundation of investigating how PNECs contribute to lung homeostasis, injury/repair, and tumorigenesis.progenitor | naphthalene | cell of origin | tumor suppressor gene

Branching morphogenesis is a fundamental program for tissue patterning. We show that active YAP, a key mediator of Hippo signaling, is distributed throughout the murine lung epithelium and loss of epithelial YAP severely disrupts branching. Failure to branch is restricted to regions where YAP activity is removed. This suggests that YAP controls local epithelial cell properties. In support of this model, mechanical force production is compromised and cell proliferation is reduced in Yap mutant lungs. We propose that defective force generation and insufficient epithelial cell number underlie the branching defects. Through genomic analysis, we also uncovered a feedback control of pMLC levels, which is critical for mechanical force production, likely through the direct induction of multiple regulators by YAP. Our work provides a molecular pathway that could control epithelial cell properties required for proper morphogenetic movement and pattern formation.DOI: http://dx.doi.org/10.7554/eLife.21130.001

Identifying cells of tumor origin is a fundamental question in tumor biology. Answers to this central question will not only advance our understanding of tumor initiation and progression but also have important therapeutic implications. In this study, we aimed to uncover the cells of origin of lung adenocarcinoma, a major subtype of non-small cell lung cancer. To this end, we developed new mouse models of lung adenocarcinoma that enabled selective manipulation of gene activity in surfactant associated protein C (SPC)-expressing cells, including alveolar type II cells and bronchioalveolar stem cells (BASCs) that reside at the bronchioalveolar duct junction (BADJ). Our findings showed that activation of oncogenic Kras alone or in combination with the removal of the tumor suppressor p53 in SPC+ cells resulted in development of alveolar tumors. Similarly, sustained EGF signaling in SPC+ cells led to alveolar tumors. By contrast, BASCs failed to proliferate or produce tumors under these conditions. Importantly, in a mouse strain in which Kras/p53 activity was selectively altered in type II cells but not BASCs, alveolar tumors developed while BADJs retained normal architecture. These results confirm and extend previous findings and support a model in which lung adenocarcinoma can initiate in alveolar type II cells. Our results establish the foundation for elucidating the molecular mechanisms by which lung cancer initiates and progresses in a specific lung cell type.

The unexpected connection between cilia and signaling is one of the most exciting developments in cell biology in the past decade. In particular, the Hedgehog (Hh) signaling pathway relies on the primary cilium to regulate tissue patterning and homeostasis in vertebrates. A central question is how ciliary localization and trafficking of Hh pathway components lead to pathway activation and regulation. In this review, we discuss recent studies that reveal the roles of ciliary regulators, components and structures in controlling the movement and signaling of Hh players. These findings significantly increase our mechanistic understanding of how the primary cilium facilitates Hh signal transduction and form the basis for further investigations to define the function of cilia in other signaling processes.

Recent advances in maximum safe glioma resection have included the introduction of a host of visualization techniques to complement intraoperative white-light imaging of tumors. However, barriers to the effective use of these techniques within the central nervous system remain. In the healthy brain, the blood-brain barrier ensures the stability of the sensitive internal environment of the brain by protecting the active functions of the central nervous system and preventing the invasion of microorganisms and toxins. Brain tumors, however, often cause degradation and dysfunction of this barrier, resulting in a heterogeneous increase in vascular permeability throughout the tumor mass and outside it. Thus, the characteristics of both the blood-brain and blood-brain tumor barriers hinder the vascular delivery of a variety of therapeutic substances to brain tumors. Recent developments in fluorescent visualization of brain tumors offer improvements in the extent of maximal safe resection, but many of these fluorescent agents must reach the tumor via the vasculature. As a result, these fluorescence-guided resection techniques are often limited by the extent of vascular permeability in tumor regions and by the failure to stain the full volume of tumor tissue. In this review, we describe the structure and function of both the blood-brain and blood-brain tumor barriers in the context of the current state of fluorescence-guided imaging of brain tumors. We discuss features of currently used techniques for fluorescence-guided brain tumor resection, with an emphasis on their interactions with the blood-brain and blood-tumor barriers. Finally, we discuss a selection of novel preclinical techniques that have the potential to enhance the delivery of therapeutics to brain tumors in spite of the barrier properties of the brain.

The chitinase 3-like 1 gene (CHI3L1) is abnormally expressed in the hippocampus of subjects with schizophrenia and may be involved in the cellular response to various environmental events that are reported to increase the risk of schizophrenia. Here, we provide evidence that the functional variants at the CHI3L1 locus influence the genetic risk of schizophrenia. First, using case-control and transmission/disequilibrium-test (TDT) methodologies, we detected a significant association between schizophrenia and haplotypes within the promoter region of CHI3L1 in two independent cohorts of Chinese individuals. Second, the at-risk CCC haplotype (P=.00058 and .0018 in case-control and TDT studies, respectively) revealed lower transcriptional activity (P=2.2 x 10(-7)) and was associated with lower expression (P=3.1 x 10(-5)) compared with neutral and protective haplotypes. Third, we found that an allele of SNP4 (rs4950928), the tagging SNP of CCC, impaired the MYC/MAX-regulated transcriptional activation of CHI3L1 by altering the transcriptional-factor consensus sequences, and this may be responsible for the decreased expression of the CCC haplotype. In contrast, the protective TTG haplotype was associated with a high level of CHI3L1 expression. Our findings identify CHI3L1 as a potential schizophrenia-susceptibility gene and suggest that the genes involved in the biological response to adverse environmental conditions are likely to play roles in the predisposition to schizophrenia.

Abstract. An Ensemble Kalman Filter (EnKF) data assimilation system was developed for a regional dust transport model. This paper applied the EnKF method to investigate modeling of severe dust storm episodes occurring in March 2002 over China based on surface observations of dust concentrations to explore the impact of the EnKF data assimilation systems on forecast improvement. A series of sensitivity experiments using our system demonstrates the ability of the advanced EnKF assimilation method using surface observed PM 10 in North China to correct initial conditions, which leads to improved forecasts of dust storms. However, large errors in the forecast may arise from model errors (uncertainties in meteorological fields, dust emissions, dry deposition velocity, etc.). This result illustrates that the EnKF requires identification and correction model errors during the assimilation procedure in order to significantly improve forecasts. Results also show that the EnKF should use a large inflation parameter to obtain better model performance and forecast potential. Furthermore, the ensemble perturbations generated at the initial time should include enough ensemble spreads to represent the background error after several assimilation cycles.