SummaryUpon injury, Müller glia cells of the zebrafish retina reprogram themselves to progenitor cells with stem cell characteristics. This necessity for retina regeneration is often compromised in mammals. We explored the significance of developmentally inevitable Sonic hedgehog signaling and found its necessity in MG reprogramming during retina regeneration. We report on stringent translational regulation of sonic hedgehog, smoothened, and patched1 by let-7 microRNA, which is regulated by Lin28a, in Müller glia (MG)-derived progenitor cells (MGPCs). We also show Shh-signaling-mediated induction of Ascl1 in mouse and zebrafish retina. Moreover, Shh-signaling-dependent regulation of matrix metalloproteinase9, in turn, regulates Shha levels and genes essential for retina regeneration, such as lin28a, zic2b, and foxn4. These observations were further confirmed through whole-retina RNA-sequencing (RNA-seq) analysis. This mechanistic gene expression network could lead to a better understanding of retina regeneration and, consequently, aid in designing strategies for therapeutic intervention in human retinal diseases.
In this paper, Newell–Whitehead–Segel equations of fractional order are solved by fractional variational iteration method. Convergence analysis and numerical examples are presented to show the efficiency of the proposed numerical method. Plotted graph demonstrate the mightiness and accurateness of the proposed technique.
SummaryHistone deacetylases (Hdacs) play significant roles in cellular homeostasis and tissue differentiation. Hdacs are well characterized in various systems for their physiological and epigenetic relevance. However, their significance during retina regeneration remains unclear. Here we show that inhibition of Hdac1 causes a decline in regenerative ability, and injury-dependent regulation of hdacs is essential for regulating regeneration-associated genes like ascl1a, lin28a, and repressors like her4.1 at the injury site. We show selective seclusion of Hdac1 from the proliferating Müller glia-derived progenitor cells (MGPCs) and its upregulation in the neighboring cells. Hdacs negatively regulate her4.1, which also represses lin28a and essential cytokines to control MGPCs proliferation. Interestingly, Hdacs' inhibition reversibly blocks regeneration through the repression of critical cytokines and other regeneration-specific genes, which is also revealed by whole-retina RNA sequence analysis. Our study shows mechanistic understanding of the Hdac pathway during zebrafish retina regeneration.
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.
In zebrafish, the damaged retina can regenerate with the help of Muller glia–derived progenitor cells. Mitra et al. show that Mycb regulates lin28a, a facilitator of regeneration, both as an activator and repressor in selected cells. Further, Mycb in collaboration with Hdac1 represses her4.1, a negative regulator of retina regeneration.
Hepatoma‐derived growth factor is a nuclear targeted mitogen containing a PWWP domain that mediates binding to DNA. To date, almost nothing is known about the molecular mechanisms of the functions of hepatoma‐derived growth factor, its routes of secretion and internalization or post‐translational modifications. In the present study, we show for the first time that hepatoma‐derived growth factor is modified by the covalent attachment of small ubiquitin‐related modifier 1 (SUMO‐1), a post‐translational modification with regulatory functions for an increasing number of proteins. Using a basal SUMOylation system in Escherichia coli followed by a MALDI‐TOF‐MS based peptide analysis, we identified the lysine residue SUMOylated located in the N‐terminal part of the protein adjacent to the PWWP domain. Surprisingly, this lysine residue is not part of the consensus motif described for SUMOylation. With a series of hepatoma‐derived growth factor mutants, we then confirmed that this unusual location is also used in mammalian cells and that SUMOylation of hepatoma‐derived growth factor takes place in the nucleus. Finally, we demonstrate that SUMOylated hepatoma‐derived growth factor is not binding to chromatin, in contrast to its unSUMOylated form. These observations potentially provide new perspectives for a better understanding of the functions of hepatoma‐derived growth factor.
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