Oct4 mediates Müller glia reprogramming and cell cycle exit during retina regeneration in zebrafish.

Poonam Sharma,Mansi Chaudhary,Shivangi Gupta,Bindia Chawla,Rajesh Ramachandran,Mohammad Anwar Khursheed,Soumitra Mitra

doi:10.26508/lsa.201900548

Poonam Sharma, Mansi Chaudhary + Show 5 more

Open Access

https://doi.org/10.26508/lsa.201900548

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Abstract

Octamer-binding transcription factor 4 (Oct4, also known as Pou5F3) is an essential pluripotency-inducing factor, governing a plethora of biological functions during cellular reprogramming. Retina regeneration in zebrafish involves reprogramming of Müller glia (MG) into a proliferating population of progenitors (MGPCs) with stem cell-like characteristics, along with up-regulation of pluripotency-inducing factors. However, the significance of Oct4 during retina regeneration remains elusive. In this study, we show an early panretinal induction of Oct4, which is essential for MG reprogramming through the regulation of several regeneration-associated factors such as Ascl1a, Lin28a, Sox2, Zeb, E-cadherin, and various miRNAs, namely, let-7a, miR-200a/miR-200b, and miR-143/miR-145 We also show the crucial roles played by Oct4 during cell cycle exit of MGPCs in collaboration with members of nucleosome remodeling and deacetylase complex such as Hdac1. Notably, Oct4 regulates Tgf-β signaling negatively during MG reprogramming, and positively to cause cycle exit of MGPCs. Our study reveals unique mechanistic involvement of Oct4, during MG reprogramming and cell cycle exit in zebrafish, which may also account for the inefficient retina regeneration in mammals.

Highlights

Tissue regeneration is a complex phenomenon in which the damaged part of the organ is restored to normalcy through a series of genetic and epigenetic transformations of cells near the injury site
Our study reveals unique mechanistic involvement of Oct4, during Müller glia (MG) reprogramming and cell cycle exit in zebrafish, which may account for the inefficient retina regeneration in mammals
We demonstrate the significance of the contrasting role of Oct4-mediated signaling events towards the later stages, which is necessary for the cell cycle exit of MG-derived progenitor cells (MGPCs) that paves way for complete regenerative response in the zebrafish retina

Summary

Introduction

Tissue regeneration is a complex phenomenon in which the damaged part of the organ is restored to normalcy through a series of genetic and epigenetic transformations of cells near the injury site. Several studies, characterizing various molecular events with special reference to transcription factors, cell signaling networks, epigenome modification, etc., have revealed the complex nature of zebrafish retina regeneration (Goldman, 2014; Gorsuch & Hyde, 2014; Wan & Goldman, 2016). Many of such regenerationassociated gene expression events were missing or inadequate in the injured mammalian retina, which may account for lack of complete retina regeneration in them (Wilken & Reh, 2016). Lack of adequate regenerative response in mammalian models necessitates a deeper investigation into the MG reprogramming of zebrafish retina, which would enable us to connect the missing links of the ever-enigmatic regeneration cascade

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