A Role for Casz1 in Regulating Rod Photoreceptor Nuclear Organization and Survival

• Main Author: Stevanovic, Milanka
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2017
• Subjects: Ablation; Cellular biology; Gene expression; Microscopy; Photoreceptors; Retina; Transcription factors
• ISBN: 9798582593966

Photoreceptors act as light-sensing units of the retina and are frequently lost in retinal degenerative diseases, which affect millions of people worldwide. Photoreceptor cell survival critically depends on the integrity of gene expression. It is therefore of importance to identify and characterize factors that protect the photoreceptor transcriptome. In this study, we show that the temporal transcription factor Casz1 is required to maintain rod photoreceptor survival in the mouse retina, notably through its role in establishing and maintaining proper nuclear organization. Conditional ablation of Casz1 in maturing rod photoreceptors led to retinal degeneration over a period of 8-12 months, implicating Casz1 as a transcription factor required for the survival of mature rods. Casz1 loss-of-function also led to ultrastructural anomalies in rods in the form of decondensed and disorganized chromatin architecture in many nuclei. On the other hand, Casz1 gain-of-function in retinal progenitor cells led to a striking inverted nucleus, resulting in a characteristic single central chromocenter reminiscent of the nuclear architecture of mature rods. Mechanistically, we found that Casz1 is necessary to oppose the function of the nuclear lamina. The rod nuclei of nocturnal mammals undergo chromatin inversion, a process in which tethers of heterochromatin at the nuclear envelope, such as Lamin A/C, are suppressed. Casz1 plays a role in suppressing these laminar proteins, as its ablation in rods leads to abnormal upregulation of Lamin A/C. Overexpressing Lamin A in rods, in turn, blocks chromatin inversion and we suggest that this may lead to photoreceptor cell death. Our data support a role for Casz1 in regulating rod photoreceptor nuclear organization and survival through its effects on the nuclear lamina.