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Mechanisms of growth control in the postembryonic medaka retina

Becker, Clara

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Abstract

Postembryonic stem cell niches are present throughout the vertebrate clade to facilitate development, homeostasis, regeneration and growth. While teleosts and amphibians display sustained stem cell activity in most organs after embryogenesis, higher vertebrates retain stem cell activity only in specific tissues. Despite these differences, similar challenges are imposed on all vertebrate organisms: new tissue has to be generated to expand or replace existent one while simultaneously ensuring integrity and functionality of the organ. Tight control of stem and progenitor cell proliferation is necessary to avoid aberrant growth such as in cancer. In the retina of the teleost medaka (Oryzias latipes), retinal stem (RSC) and progenitor (RPC) cells are located in the ciliary marginal zone (CMZ) and mediate postembryonic growth and neurogenesis. Since function and shape of the eye are intimately linked, the activity of RSCs and RPCs is tightly coordinated to establish proper cell type composition and number. In this thesis I addressed intrinsic and extrinsic regulation mechanisms of the RSC niche. I hypothesised that retinal growth underlies intrinsically active growth factor signaling, and that immune cells safeguard the RSC niche in homeostasis and injury. To analyse intrinsic regulation of RSC proliferation, I assessed the function of insulin-like growth factor (Igf) signaling in the CMZ using gain- and loss- of-function approaches. I found that Igf1 receptor over-activation increased cell cycle speed, RPC number and consequently retinal size, while simultaneously preserving the stereotypical retinal architecture. Strikingly, RSCs were not susceptible to mitogenic stimuli, indicating that RPC amplification is the determinant of retinal size and composition. To understand the extrinsic regulation of the RSC niche, I examined the interplay of immune cells and RSCs. I found that Ccl25b-positive RSCs are phagocytosed by Ccr9a-positive immune cells located in the CMZ. Ccl25b mutation abrogates reactivation of immune cells upon RSC injury, implicating Ccl25b–Ccr9a signaling in the immune–stem cell interaction during homeostatic surveillance and injury response. In summary, my results propose that accurate postembryonic growth and tissue integrity depend on both cell intrinsic and extrinsic mechanisms of growth control in the RSC niche of medaka.

Item Type: Dissertation
Supervisor: Wittbrodt, Prof. Dr. Joachim
Place of Publication: Heidelberg
Date of thesis defense: 22 November 2019
Date Deposited: 27 Nov 2019 07:18
Date: 2020
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
Subjects: 500 Natural sciences and mathematics
570 Life sciences
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