Knockdown of CXCL14 disrupts neurovascular patterning during ocular development

Ojeda, Ana F.; Munjaal, Ravi P.; Lwigale, Peter Y.

doi:10.1016/j.ydbio.2017.01.008

Cited by 15 publications

(10 citation statements)

References 60 publications

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“…The net regulatory effect of the above transcription factors determines corneal morphogenesis. This includes formation of the collagen ultrastructure, proliferation and differentiation of the cellular layers, and neurovascular patterning 5,6,61. Therefore, we analyzed the expression of critical components of corneal development, including genes for the ECM, matrix remodeling proteins, ECM receptors, cell junction proteins, epithelial development, cell cycle, and neurovascular patterning.…”

Section: Resultsmentioning

confidence: 99%

Transformation of the Transcriptomic Profile of Mouse Periocular Mesenchyme During Formation of the Embryonic Cornea

Lwigale

2019

Invest. Ophthalmol. Vis. Sci.

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PurposeDefects in neural crest development are a major contributing factor in corneal dysgenesis, but little is known about the genetic landscape during corneal development. The purpose of this study was to provide a detailed transcriptome profile and evaluate changes in gene expression during mouse corneal development.MethodsRNA sequencing was used to uncover the transcriptomic profile of periocular mesenchyme (pNC) isolated at embryonic day (E) 10.5 and corneas isolated at E14.5 and E16.5. The spatiotemporal expression of several differentially expressed genes was validated by in situ hybridization.ResultsAnalysis of the whole-transcriptome profile between pNC and embryonic corneas identified 3815 unique differentially expressed genes. Pathway analysis revealed an enrichment of differentially expressed genes involved in signal transduction (retinoic acid, transforming growth factor-β, and Wnt pathways) and transcriptional regulation.ConclusionsOur analyses, for the first time, identify a large number of differentially expressed genes during progressive stages of mouse corneal development. Our data provide a comprehensive transcriptomic profile of the developing cornea. Combined, these data serve as a valuable resource for the identification of novel regulatory networks crucial for the advancement of studies in congenital defects, stem cell therapy, bioengineering, and adult corneal diseases.

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Section: Resultsmentioning

confidence: 99%

Transformation of the Transcriptomic Profile of Mouse Periocular Mesenchyme During Formation of the Embryonic Cornea

Lwigale

2019

Invest. Ophthalmol. Vis. Sci.

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“…Of interest, CXCL14 and CXCL12 are the most highly conserved members of the large family of chemokines and mice lacking these chemokines have severe developmental defects [reviewed in McCully et al and Nagasawa ( 1 , 60 )]. It is possible that CXCL14 and CXCL12 synergize during organ development, including neurovascular patterning ( 61 ), eye ( 62 ) and connective tissue ( 63 ) formation, where both chemokines are prominently expressed. Of interest, both chemokines were shown to activate fibroblasts, suggesting that CXCL14 and CXCL12 may co-operate in controlling fibroblast functions in various scenarios, including tissue repair, fibrosis ( 23 – 25 ) and tumor progression ( 27 , 28 , 64 ).…”

Section: Discussionmentioning

confidence: 99%

CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems

et al. 2020

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Reflecting their importance in immunity, the activity of chemokines is regulated on several levels, including tissue and context-specific expression and availability of their cognate receptor on target cells. Chemokine synergism, affecting both chemokine and chemokine receptor function, has emerged as an additional control mechanism. We previously demonstrated that CXCL14 is a positive allosteric modulator of CXCR4 in its ability to synergize with CXCL12 in diverse cellular responses. Here, we have extended our study to additional homeostatic, as well as a selection of inflammatory chemokine systems. We report that CXCL14 strongly synergizes with low (sub-active) concentrations of CXCL13 and CCL19/CCL21 in in vitro chemotaxis with immune cells expressing the corresponding receptors CXCR5 and CCR7, respectively. CXCL14 by itself was inactive, not only on cells expressing CXCR5 or CCR7 but also on cells expressing any other known conventional or atypical chemokine receptor, as assessed by chemotaxis and/or β-arrestin recruitment assays. Furthermore, synergistic migration responses between CXCL14 and inflammatory chemokines CXCL10/CXCL11 and CCL5, targeting CXCR3 and CCR5, respectively, were marginal and occasional synergistic Ca 2+ flux responses were observed. CXCL14 bound to 300-19 cells and interfered with CCL19 binding to CCR7-expressing cells, suggesting that these cellular interactions contributed to the reported CXCL14-mediated synergistic activities. We propose a model whereby tissue-expressed CXCL14 contributes to cell localization under steady-state conditions at sites with prominent expression of homeostatic chemokines.

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“…For example, CXCL14 , which was associated with variation in the eye region, plays a critical role in ocular tissues during development [ 46 – 48 ]. Knockdown of CXCL14 led to eyelid and mandibular defects in about a third of chick embryos, which is consistent with its expression in eyelid ectoderm and the first branchial arch [ 47 ]. We also identified new signals near biologically plausible genes at previously reported loci.…”

Section: Discussionmentioning

confidence: 53%

Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations

et al. 2021

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Facial morphology is highly variable, both within and among human populations, and a sizable portion of this variation is attributable to genetics. Previous genome scans have revealed more than 100 genetic loci associated with different aspects of normal-range facial variation. Most of these loci have been detected in Europeans, with few studies focusing on other ancestral groups. Consequently, the degree to which facial traits share a common genetic basis across diverse sets of humans remains largely unknown. We therefore investigated the genetic basis of facial morphology in an East African cohort. We applied an open-ended data-driven phenotyping approach to a sample of 2,595 3D facial images collected on Tanzanian children. This approach segments the face into hierarchically arranged, multivariate features that capture the shape variation after adjusting for age, sex, height, weight, facial size and population stratification. Genome scans of these multivariate shape phenotypes revealed significant (p < 2.5 × 10−8) signals at 20 loci, which were enriched for active chromatin elements in human cranial neural crest cells and embryonic craniofacial tissue, consistent with an early developmental origin of the facial variation. Two of these associations were in highly conserved regions showing craniofacial-specific enhancer activity during embryological development (5q31.1 and 12q21.31). Six of the 20 loci surpassed a stricter threshold accounting for multiple phenotypes with study-wide significance (p < 6.25 × 10−10). Cross-population comparisons indicated 10 association signals were shared with Europeans (seven sharing the same associated SNP), and facilitated fine-mapping of causal variants at previously reported loci. Taken together, these results may point to both shared and population-specific components to the genetic architecture of facial variation.

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Knockdown of CXCL14 disrupts neurovascular patterning during ocular development

Cited by 15 publications

References 60 publications

Transformation of the Transcriptomic Profile of Mouse Periocular Mesenchyme During Formation of the Embryonic Cornea

Transformation of the Transcriptomic Profile of Mouse Periocular Mesenchyme During Formation of the Embryonic Cornea

CXCL14 Preferentially Synergizes With Homeostatic Chemokine Receptor Systems

Genome scans of facial features in East Africans and cross-population comparisons reveal novel associations

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