Modulation of retinal progenitors : A bird’s-eye view of retinal regeneration and disease

Sammanfattning: The cell populations of the retina and their intricate organization provide us with one of the most important senses – vision. All retinal cell populations are derived from a common progenitor pool as a result of tight regulation of proliferation, differentiation, dedifferentiation, and programmed cell death. Dysregulation of these processes, or injury to the retina, can result in loss of vision or in certain cases even cancer – i.e. retinoblastoma. Understanding the mechanistic basis of these processes allows for modeling cancer and retinal regeneration. To this purpose, the embryonic chicken retina, and cultures thereof, were subjected to pharmacological intervention and modulation of gene expression. To validate findings in a human model, some studies were extended with the use of human cell cultures or retinal organoids derived from human embryonic stem cells. The focus was on the late events of retinal neurogenesis. In Paper I, we investigated endothelins as potential modulators of injury-induced retinal regeneration, which is performed by Müller cells in certain species. Injured Müller cells will dedifferentiate and return to the progenitor pool. We found that stimulation of the endothelin receptor induces dedifferentiation by transactivation of the epidermal growth factor receptor and subsequent activation of the MAPK-signaling pathway, in both chicken Müller cells and an immortalized cell line with Müller cell properties. Our findings show that endothelins have potential as possible regulators of the injury response and subsequent regeneration of lost neurons performed by Müller cells.In Paper II, the Nolz1 transcription factor and its regulation of retinal neurogenesis was explored. We show that Nolz1 acts as a negative regulator of the cell cycle in retinal progenitors, and hinders bipolar cell specification by Lim3 gene repression.In Paper III, we investigated the final neurogenic mitosis of the cone photoreceptor/horizontal cell progenitor (cPR/HC) lineage. MYCN-overexpression in a functional RB1 setting produced neoplastic growth in a cell-type and developmental-stage specific manner. The cPR/HC-lineage alone escaped apoptosis and continued proliferation both in human retinal organoids and embryonic chicken retina. Our findings have implications for the etiology of retinoblastoma and show that MYCN alone can induce cancerogenesis. The tumors arise as a result if intrinsic properties of the cPR/HC-lineage, which have not been observed in other retinal populations. Taken together, this thesis gives novel knowledge regarding the late events of retinal neurogenesis, cell-type specification, and the inherent properties of certain retinal progenitor lineages in the healthy and diseased retina.