The molecular mechanisms that sort migrating neural crest cells (NCCs) along a shared pathway into two functionally discrete structures, the dorsal root ganglia and sympathetic ganglia (SGs), are ...unknown. We report here that this patterning is attributable in part to differential expression of the chemokine receptor, CXCR4. We show that (1) a distinct subset of ventrally migrating NCCs express CXCR4 and this subset is destined to form the neural core of the sympathetic ganglia, and (2) the CXCR4 ligand, SDF-1, is a chemoattractant for NCCs in vivo and is expressed adjacent to the future SGs. Reduction of CXCR4 expression in NCCs disrupts their migration toward the future SGs, whereas overexpression of CXCR4 in non-SG-destined NCCs induces them to migrate aberrantly toward the SGs. These data are the first to demonstrate a major role for chemotaxis in the patterning of NCC migration and demonstrate the neural crest is composed of molecularly heterogeneous cell populations.
The neural crest is an excellent model to study embryonic cell migration, since cell behaviors can be studied in vivo with advanced optical imaging and molecular intervention. What is unclear is how ...molecular signals direct neural crest cell (NCC) migration through multiple microenvironments and into specific targets. Here, we tested the hypothesis that the invasion of cranial NCCs, specifically the rhombomere 4 (r4) migratory stream into branchial arch 2 (ba2), is due to chemoattraction through neuropilin-1–vascular endothelial growth factor (VEGF) interactions. We found that the spatio-temporal expression pattern of VEGF in the ectoderm correlated with the NCC migratory front. RT-PCR analysis of the r4 migratory stream showed that ba2 tissue expressed VEGF and r4 NCCs expressed VEGF receptor 2. When soluble VEGF receptor 1 (sVEGFR1) was injected distal to the r4 migratory front, to bind up endogenous VEGF, NCCs failed to completely invade ba2. Time-lapse imaging revealed that cranial NCCs were attracted to ba2 tissue or VEGF sources in vitro. VEGF-soaked beads or VEGF-expressing cells placed adjacent to the r4 migratory stream caused NCCs to divert from stereotypical pathways and move towards an ectopic VEGF source. Our results suggest a model in which NCC entry and invasion of ba2 is dependent on chemoattractive signaling through neuropilin-1-VEGF interactions.
The purpose of the study was to determine allometric exponents for scaling grip strength in children that effectively control for body mass (BM) and stature (Ht) and to develop normative grip ...strength data for Hawaiian children. One thousand, four hundred thirty-seven students (754 boys) from a rural community in Hawaii participated in this 5-year study, resulting in 2,567 data points. Handgrip strength, BM, and Ht were collected every year. Multiple log-linear regression was used to determine allometric exponents for BM and Ht. Appropriateness of the allometric model was assessed through regression diagnostics, including normality of residuals and homoscedasticity. Allometrically scaled, ratio-scaled, and unscaled grip strength were then correlated with BM and Ht to examine the effectiveness of the procedure in controlling for body size. Allometric exponents for BM and Ht were calculated separately for each age group of boys and girls to satisfy the common exponent and group difference principles described by Vanderburgh. Unscaled grip strength had moderate to strong positive correlations with BM and Ht (p ≤ 0.05 for all) for all age groups. Ratio-scaled handgrip strength had significant moderate to strong negative correlations with BM (p ≤ 0.05 for all) and, to a lesser extent, Ht (p ≤ 0.05 for 8- to 12-year-old boys; p ≤ 0.05 for 8- to 12- and 14-year-old girls). Correlations between allometrically scaled handgrip strength and BM and Ht were not significant and approached zero. This study was the first to allometrically scale handgrip strength for BM and Ht in Hawaiian children. Allometric scaling applied to grip strength provides a useful expression of grip strength free of the confounding influence of body size.
Melanoma pathogenesis from normal neural crest-derived melanocytes is often fatal due to aggressive cell invasion throughout the body. The identification of signals that reprogram de-differentiated, ...metastatic melanoma cells to a less aggressive and stable phenotype would provide a novel strategy to limit disease progression. In this study, we identify and test the function of developmental signals within the chick embryonic neural crest microenvironment to reprogram and sustain the transition of human metastatic melanoma to a neural crest cell-like phenotype. Results reveal that co-culture of the highly aggressive and metastatic human melanoma cell line C8161 upregulate a marker of melanosome formation (Mart-1) in the presence of embryonic day 3.5 chick trunk dorsal root ganglia. We identify nerve growth factor (NGF) as the signal within this tissue driving Mart-1 re-expression and show that NGF receptors trkA and p75 cooperate to induce Mart-1 re-expression. Furthermore, Mart-1 expressing C8161 cells acquire a gene signature of poorly aggressive C81-61 cells. These data suggest that targeting NGF signaling may yield a novel strategy to reprogram metastatic melanoma toward a benign cell type.
New drugs and biologics have had a tremendous impact on the treatment of many diseases. However, available measures suggest that pharmaceutical innovation has remained relatively flat, despite ...substantial growth in research and development spending. We review recent literature on pharmaceutical innovation to identify limitations in measuring and assessing innovation, and we describe the framework and collaborative approach we are using to develop more comprehensive, publicly available metrics for innovation. Our research teams at the Brookings Institution and Deerfield Institute are collaborating with experts from multiple areas of drug development and regulatory review to identify and collect comprehensive data elements related to key development and regulatory characteristics for each new molecular entity approved over the past several decades in the United States and the European Union. Subsequent phases of our effort will add data on downstream product use and patient outcomes and will also include drugs that have failed or been abandoned in development. Such a database will enable researchers to better analyze the drivers of drug innovation, trends in the output of new medicines, and the effect of policy efforts designed to improve innovation.
The role of chemotaxis in neural crest migration Kulesa, Paul M; Kasemeier‐Kulesa, Jennifer C; McLennan, Rebecca ...
The FASEB journal,
April 2011, 2011-04-00, Volume:
25, Issue:
S1
Journal Article
Peer reviewed
Neural crest (NC) cells travel long distances throughout the embryo to reach precise target sites and contribute to many tissues including the peripheral nervous system. During peripheral nervous ...system development, a common pool of NC cells is distributed into two functionally discrete structures, the dorsal root ganglia (DRG) and sympathetic ganglia (SG), yet it has remained unclear how cells are driven to these targets and differentiate into appropriate cell types. We will show that this patterning is due in part to differential expression of the chemokine receptor, CXCR4. We will present evidence that 1) a distinct subset of ventrally‐migrating NC cells express CXCR4 and this subset is destined to form the neural core of the SG and 2) the CXCR4 ligand, SDF‐1, is a chemoattractant for NC cells in vivo, and is expressed adjacent to the future SG. Reduction of CXCR4 expression in NC cells disrupts their migration towards the future SG while overexpression of CXCR4 in non‐SG destined NC cells induces them to migrate aberrantly towards the SG. These data demonstrate a major role for chemotaxis in the patterning of trunk NC cell migration.
This work was supported by NSF Grant IOS‐0719251 and the Stowers Institute for Medical Research.
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