A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration

Lau, Stephanie; Feitzinger, Anna A; Venkiteswaran, Gayatri; Wang, John; Lewellis, Stephen W.; Koplinski, Chad A.; Peterson, Francis C.; Volkman, Brian F.; Meier‐Schellersheim, Martin; Knaut, Holger

doi:10.1038/s41556-020-0465-4

Cited by 45 publications

(46 citation statements)

References 38 publications

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“…Three lines of zebrafish (Danio rerio) were used in this study: AB strain zebrafish bred in our facility from founders originally purchased from ZIRC (Eugene, Oregon), transgenic cxcr4b:cxcr4b‐EGFP‐IRES‐kate2‐CaaX (Lau et al, 2020; Venkiteswaran et al, 2013) zebrafish, and transgenic HuC:GFP (Park et al, 2000) zebrafish, which were generously gifted to us (see Acknowledgments). AB zebrafish were used as a wild‐type strain and for their lack of transgenic expression.…”

Section: Methodsmentioning

confidence: 99%

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

Collier

Khalizova

Chang

et al. 2020

Alcoholism Clin & Exp Res

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Background: Embryonic exposure to ethanol (EtOH) produces marked disturbances in neuronal development and alcohol-related behaviors, with low-moderate EtOH doses stimulating neurogenesis without producing apoptosis and high doses having major cytotoxic effects while causing gross morphological abnormalities. With the pro-inflammatory chemokine system, Cxcl12, and its main receptor Cxcr4, known to promote processes of neurogenesis, we examined here this neuroimmune system in the embryonic hypothalamus to test directly if it mediates the stimulatory effects low-moderate EtOH doses have on neuronal development. Methods: We used the zebrafish (Danio rerio) model, which develops externally and allows one to investigate the developing brain in vivo with precise control of dose and timing of EtOH delivery in the absence of maternal influence. Zebrafish were exposed to low-moderate EtOH doses (0.1, 0.25, 0.5% v/ v), specifically during a period of peak hypothalamic development from 22 to 24 hours postfertilization, and in some tests were pretreated from 2 to 22 hpf with the Cxcr4 receptor antagonist, AMD3100. Measurements in the hypothalamus at 26 hpf were taken of cxcl12a and cxcr4b transcription, signaling, and neuronal density using qRT-PCR, RNAscope, and live imaging of transgenic zebrafish. Results: Embryonic EtOH exposure, particularly at the 0.5% dose, significantly increased levels of cxcl12a and cxcr4b mRNA in whole embryos, number of cxcl12a and cxcr4b transcripts in developing hypothalamus, and internalization of Cxcr4b receptors in hypothalamic cells. Embryonic EtOH also caused an increase in the number of hypothalamic neurons and coexpression of cxcl12a and cxcr4b transcripts within these neurons. Each of these stimulatory effects of EtOH in the embryo was blocked by pretreatment with the Cxcr4 antagonist AMD3100. Conclusions: These results provide clear evidence that EtOH's stimulatory effects at low-moderate doses on the number of hypothalamic neurons early in development are mediated, in part, by increased transcription and intracellular activation of this chemokine system, likely due to autocrine signaling of Cxcl12a at its Cxcr4b receptor within the neurons.

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Section: Methodsmentioning

confidence: 99%

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

Collier

Khalizova

Chang

et al. 2020

Alcoholism Clin & Exp Res

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“…CXCR4 and integrin might synergistically promote lymphatic metastasis in lung cancer, and might act as clinical predictors of lymph node metastasis in NSCLC [38][39][40]. High expression levels of chemokines are related to a poor prognosis and chemotherapy tolerance in cancer patients [41][42][43][44]. CXCR4 is a chemokine receptor that plays a critical role in the process of lymphocyte homing to lymphatic vessels and secondary lymphoid organs, including the lymph nodes [45].…”

Section: Discussionmentioning

confidence: 99%

99mTc-Galacto-RGD2 Integrin αvβ3 Targeted Imaging as a Surrogate for Molecular Phenotyping in Lung Cancer: Prospective Study in the Real World

Fu¹,

Yan²,

Fu³

et al. 2021

Preprint

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Purpose: Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are beneficial in patients with lung cancer. We explored the clinical value of 99mTc-Galacto-RGD2 single-photon emission computed tomography (SPECT/CT) in patients with lung cancer, Integrin αvβ3 expression, and neovascularization in lung cancer subtypes was also addressed. Methods: A total of 185 patients with lung cancer and 25 patients with benign lung diseases were enrolled in this prostective study from January 2013 to December 2016. All patients underwent 99mTc-Galacto-RGD2 imaging. The region of interest was drawn around each primary lesion, and tumour uptake of 99mTc-Galacto-RGD2 was measured as the tumour/normal tissue ratio（T/N）. The diagnostic efficacy was evaluated by receiver operating characteristic curve analysis. Tumour tissues were obtained from 66 patients with malignant diseases and seven with benign disease. Tumour expression levels of αvβ3, CD31, Ki-67, and CXCR4 were analysed to determine their value for phenotyping and metastasis potential evaluation. Results: The lung cancer patients included 22 cases of small cell lung cancer (SCLC), 48 squamous cell carcinoma (LSC), 97 adenocarcinoma (LAC), and 18 other types of lung cancer. The sensitivity, specificity, and accuracy of 99mTc-Galacto-RGD2 SPECT/CT using a cut-off value of 2.5 were 91.89 %, 48.0 %, and 86.67 %, respectively. Integrin αvβ3 expression was higher in non-SCLC compared with SCLC, while LSC showed denser neovascularization and higher integrin αvβ3 expression. Integrin αvβ3 expression levels were significantly higher in advanced (Ⅲ, Ⅳ) than early stages (Ⅰ, Ⅱ). However, there was no significant correlation between tumour uptake and αvβ3 expression. Conclusion: 99mTc-Galacto-RGD2 SPECT/CT has high sensitivity but limited specificity for detecting primary lung cancer. RGD imaging may help evaluate the biological behaviour and phenotyping, and thus aid management in lung cancer.

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“…S8 online). The role of CXCR7 in shaping CXCL12 gradient has been demonstrated in zebrafish, and by using novel fluorescence-based sensors of CXCL12 signalling, CXCL12 gradient and its dynamics have been directly demonstrated in vivo 37 , 59 – 61 . Developing similar technologies in mice to enable high resolution and quantitative analyses of the distribution of signalling CXCL12 would be useful to directly address the role of CXCL12 in regulating anterior-to ventral turning of PN neurons.…”

Section: Discussionmentioning

confidence: 99%

Chemokine receptor CXCR7 non-cell-autonomously controls pontine neuronal migration and nucleus formation

Zhu

Hirata

Mackay

et al. 2020

Sci Rep

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Long distance tangential migration transports neurons from their birth places to distant destinations to be incorporated into neuronal circuits. How neuronal migration is guided during these long journeys is still not fully understood. We address this issue by studying the migration of pontine nucleus (PN) neurons in the mouse hindbrain. PN neurons migrate from the lower rhombic lip first anteriorly and then turn ventrally near the trigeminal ganglion root towards the anterior ventral hindbrain. Previously we showed that in mouse depleted of chemokine receptor CXCR4 or its ligand CXCL12, PN neurons make their anterior-to-ventral turn at posteriorized positions. However, the mechanism that spatiotemporally controls the anterior-to-ventral turning is still unclear. Furthermore, the role of CXCR7, the atypical receptor of CXCL12, in pontine migration has yet to be examined. Here, we find that the PN is elongated in Cxcr7 knockout due to a broadened anterior-to-ventral turning positions. Cxcr7 is not expressed in migrating PN neurons en route to their destinations, but is strongly expressed in the pial meninges. Neuroepithelium-specific knockout of Cxcr7 does not recapitulate the PN phenotype in Cxcr7 knockout, suggesting that CXCR7 acts non-cell-autonomously possibly from the pial meninges. We show further that CXCR7 regulates pontine migration by modulating CXCL12 protein levels. During development new born neurons migrate radially or tangentially from the progenitor zones to their final destinations 1-4. Tangential migration is often deployed by neurons that migrate over long distances, sometimes across brain compartments, to distant destinations 5-7. Such long-distance tangential migration usually involves multiple changes of migratory directions through varied tissue environments, hence demands a complex set of underlying guidance mechanisms. While much has been learned of the guidance of tangential migration owing in part to its shared mechanisms with the guidance of growing axons 2,8-10 , mechanisms that underlie changes of migratory directions are still incompletely understood. The migration of PN neurons in the mouse hindbrain is an excellent model to investigate the guidance mechanisms underlying long-distance tangential migration 11-16. PN neurons are destined to form the pontine nuclei, an amalgamation of pontine gray nucleus and reticular tegmental nucleus, which form a part of the precerebellar system that relays information from the rest of the CNS to the cerebellum 17-19. These neurons are born from the lower rhombic lip, a progenitor zone lining the dorsal edge of the posterior hindbrain (Fig. 1) 20-24. They then migrate anteriorly over the pial surface of the hindbrain beneath the pial meninges (Fig. 1) 11,17,25. At the level of the root of the trigeminal ganglion (gV), anteriorly migrating PN neurons make a sharp turn ventrally, heading orthogonally towards the ventral midline (Fig. 1) 13,26. Near the ventral midline, most PN neurons detach from the migratory stream without crossing the midline and...

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A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration

Cited by 45 publications

References 38 publications

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

Involvement of Cxcl12a/Cxcr4b Chemokine System in Mediating the Stimulatory Effect of Embryonic Ethanol Exposure on Neuronal Density in Zebrafish Hypothalamus

99mTc-Galacto-RGD2 Integrin αvβ3 Targeted Imaging as a Surrogate for Molecular Phenotyping in Lung Cancer: Prospective Study in the Real World

Chemokine receptor CXCR7 non-cell-autonomously controls pontine neuronal migration and nucleus formation

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