June 2021
Volume 62, Issue 8
Open Access
ARVO Annual Meeting Abstract  |   June 2021
Genetic variability of lymphangiogenesis in Collaborative Cross mice: a powerful tool to identify novel endogenous regulators of lymphangiogenesis
Author Affiliations & Notes
  • Thomas Clahsen
    University Hospital Cologne Centre of Ophthalmology, Klinikum der Universitat zu Koln Zentrum fur Augenheilkunde, Koln, Nordrhein-Westfalen, DE, academic/hospital, Germany
  • Christian Büttner
    Universitatsklinikum Erlangen Institut fur Humangenetik, Erlangen, Bayern, Germany
  • Niloofar Hatami
    University Hospital Cologne Centre of Ophthalmology, Klinikum der Universitat zu Koln Zentrum fur Augenheilkunde, Koln, Nordrhein-Westfalen, DE, academic/hospital, Germany
  • Felix Nüst
    University Hospital Cologne Centre of Ophthalmology, Klinikum der Universitat zu Koln Zentrum fur Augenheilkunde, Koln, Nordrhein-Westfalen, DE, academic/hospital, Germany
  • Tim Gabriel
    University Hospital Cologne Centre of Ophthalmology, Klinikum der Universitat zu Koln Zentrum fur Augenheilkunde, Koln, Nordrhein-Westfalen, DE, academic/hospital, Germany
  • André Reis
    Universitatsklinikum Erlangen Institut fur Humangenetik, Erlangen, Bayern, Germany
  • Claus Cursiefen
    University Hospital Cologne Centre of Ophthalmology, Klinikum der Universitat zu Koln Zentrum fur Augenheilkunde, Koln, Nordrhein-Westfalen, DE, academic/hospital, Germany
  • Footnotes
    Commercial Relationships   Thomas Clahsen, None; Christian Büttner, None; Niloofar Hatami, None; Felix Nüst, None; Tim Gabriel, None; André Reis, None; Claus Cursiefen, None
  • Footnotes
    Support  DFG Grant Cl751/1-1
Investigative Ophthalmology & Visual Science June 2021, Vol.62, 896. doi:
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      Thomas Clahsen, Christian Büttner, Niloofar Hatami, Felix Nüst, Tim Gabriel, André Reis, Claus Cursiefen; Genetic variability of lymphangiogenesis in Collaborative Cross mice: a powerful tool to identify novel endogenous regulators of lymphangiogenesis. Invest. Ophthalmol. Vis. Sci. 2021;62(8):896.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Lymphangiogenesis is involved in several diseases like corneal graft rejection, tumor metastasis, and dry eye disease. The healthy cornea is an avascular and alymphatic tissue with a distinct limbal lymphatic vascular arcade. The genetic background significantly influences the architecture of this limbal lymphatic arcade and of corneal lymphangiogenesis. The Collaborative Cross (CC) population is a large panel of recombinant inbred mouse strains derived from a genetically diverse set of eight founder strains.

Methods : Using the lymphatic vessel architecture at the limbal border of the normally avascular cornea, a quantitative trait under strong genetic influence, was used here as a model system to identify new candidate genes regulating lymphangiogenesis. Quantitative trait locus (QTL) analysis was used to combine phenotypic information (e.g. vessel area) and genotypic data (e.g. molecular markers) to reveal possible candidate genes contributing to the observed variation in the analyzed trait. Whole mounts of naïve corneas from 9 different CC mice were stained with the lymphatic vessel marker LYVE-1. The vessel area, number of branching points, endpoints, and sprouts were analyzed using cellF.

Results : The comparison of the different CC strains showed a significant difference in lymph vessel area between the CC mice and the high-lymphangiogenic C57BL/6 mice. We identified CC lines showing significantly lower lymphatic vascularized area, whereas other lines showed significantly higher lymphatic vascularized area compared with C57BL/6 mice. In the QTL analysis, we identified eight loci with a LOD score >5 associated with the morphometric parameters investigated which contain promising genes. For instance, we identified on chromosome 7 two loci, one of them harboring tyrosinase, thus confirming the results from earlier C57BL/6 x BALB/c intercross and validating the approach using CC mouse lines.

Conclusions : Using CC mice we identified several new loci associated with the morphometric parameter that contain promising genes that may play important roles in the regulation of lymphangiogenesis. Overall, our findings show that CC mice are a valid and powerful tool for the identification of new endogenous modulators of lymphangiogenesis. These modulators may serve as novel therapeutic targets for eye diseases associated with pathologic lymphangiogenesis.

This is a 2021 ARVO Annual Meeting abstract.

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