Search

During a developmental period that extends postnatally in the mouse, proliferating multipotent retinal progenitor cells produce one of 7 major cell types (rod, cone, bipolar, horizontal, amacrine, ganglion, and Muller glial cells) as they exit the cell cycle in consecutive waves. Cell production in the retina is tightly regulated by intrinsic, extrinsic, spatial, and temporal cues, and is coupled to the timing of cell cycle exit. Arsenic-resistance protein 2 (ARS2, also known as SRRT) is a component of the nuclear cap-binding complex involved in RNA Polymerase II transcription, and is required for cell cycle progression. We show that postnatal retinal progenitor cells (RPCs) require ARS2 for proper progression through S phase, and ARS2 disruption leads to early exit from the cell cycle. Furthermore, we observe an increase in the proportion of cells expressing a rod photoreceptor marker, and a loss of Muller glia marker expression, indicating a role for ARS2 in regulating cell fate specification or differentiation. Knockdown of Flice Associated Huge protein (FLASH), which interacts with ARS2 and is required for cell cycle progression and 3'-end processing of replication-dependent histone transcripts, phenocopies ARS2 knockdown. These data implicate ARS2--FLASH-mediated histone mRNA processing in regulating RPC cell cycle kinetics and neuroglial cell fate specification during postnatal retinal development. Key words: Ars2, retina, retinal progenitor cells, cell cycle, photoreceptor cells, Muller cells. Durant une periode developpementale qui s'etend a la periode postnatale chez la souris, les cellules souches retiniennes multipotentes en proliferation donnent naissance a un des sept types principaux de cellules (batonnets, cones, cellules bipolaires, cellules horizontales, cellules amacrines, cellules ganglionnaires et cellules gliales de Muller) au fur et a mesure de leur sortie du cycle cellulaire par vagues consecutives. La production de cellules dans la retine est etroitement regulee par des signaux intrinseques, extrinseques, spatiaux et temporels et elle est couplee au moment du deroulement de la sortie du cycle cellulaire. ARS2 (aussi connue comme SRRT) est une composante du complexe nucleaire de liaison de la coiffe impliquee dans la transcription par l'ARN polymerase II, et elle est requise a la progression du cycle cellulaire. Les auteurs montrent que les cellules souches retiniennes postnatales requierent ARS2 afin de progresser adequatement a travers la phase S, et que le dereglement d'ARS2 donne lieu a une sortie hative du cycle cellulaire. De plus, ils observent une augmentation de la proportion de cellules qui expriment un marqueur des batonnets, et une perte d'expression d'un marqueur des cellules gliales de Muller, indiquant qu'ARS2 pourrait jouer un role dans la regulation de la specification de la destinee cellulaire ou la differenciation. Le knockdown de FLASH, qui interagit avec ARS2 et qui est necessaire a la progression du cycle cellulaire et a la maturation de l'extremite 3' des transcrits d'histones dependants de la replication, est une phenocopie du knockdown d'ARS2. Ces donnees impliquent la maturation de l'ARNm des histones mediee par ARS2--FLASH dans la regulation de la cinetique du cycle cellulaire des cellules souches retiniennes et dans la specification de la destinee cellulaire neurogliale durant le developpement retinien postnatal. [Traduit par la Redaction] Mots-cles : Ars2, retine, cellules souches retiniennes, cycle cellulaire, photorecepteurs, cellules de Muller., Introduction Arsenic-resistance protein 2 [ARS2, also known as SRRT (Serrate RNA effector molecule)], is a stable component of the nuclear cap-binding complex and is required for the processing and transport [...]

Eosinophils are present in the thymus of mammals, yet their function at this site during homeostatic development is unknown. We used flow cytometry to determine the abundance and phenotype of eosinophils (here defined as SSchigh SiglecF+ CD11b+ CD45+ cells) in the thymus of mice during the neonatal period, the later postnatal period, and into adulthood. We show that both the total number of thymic eosinophils and their frequency among leukocytes increase over the first 2 wk of life and that their accumulation in the thymus is dependent on the presence of an intact bacterial microbiota. We report that thymic eosinophils express the interleukin-5 receptor (CD125), CD80, and IDO, and that subsets of thymic eosinophils express CD11c and major histocompatibility complex II (MHCII). We found that the frequency of MHCII-expressing thymic eosinophils increases over the first 2 wk of life, and that during this early-life period the highest frequency of MHCII-expressing thymic eosinophils is located in the inner medullary region. These data suggest a temporal and microbiota-dependent regulation of eosinophil abundance and functional capabilities in the thymus. [ABSTRACT FROM AUTHOR]

Mutations in methyl-CpG binding protein 2 (MeCP2), such as the T158M, P152R, R294X, and R306C mutations, are responsible for most Rett syndrome (RTT) cases. These mutations often result in altered protein expression that appears to correlate with changes in the nuclear size; however, the molecular details of these observations are poorly understood. Using a C2C12 cellular system expressing human MeCP2-E1 isoform as well as mouse models expressing these mutations, we show that T158M and P152R result in a decrease in MeCP2 protein, whereas R306C has a milder variation, and R294X resulted in an overall 2.5 to 3 fold increase. We also explored the potential involvement of the MeCP2 PEST domains in the proteasome-mediated regulation of MeCP2. Finally, we used the R294X mutant to gain further insight into the controversial competition between MeCP2 and histone H1 in the chromatin context. Interestingly, in R294X, MeCP2 E1 and E2 isoforms were differently affected, where the E1 isoform contributes to much of the overall protein increase observed, while E2 decreases by half. The modes of MeCP2 regulation, thus, appear to be differently regulated in the two isoforms., (© The Author(s) 2024. Published by Oxford University Press.)

Aniridia is a rare congenital syndrome that is associated with reduced visual acuity and progressive loss of vision. Aniridia patients may also develop systemic health issues associated with defects in the pancreas, digestive, and central nervous systems. The spectrum of symptoms associated with aniridia is due to haploinsufficiency of the paired box 6 gene (PAX6) and its role in the development and maintenance of the affected tissues. Here, we isolated pancreatic islets from mice heterozygous for Pax6 to test whether a Pax6-specific miRNA suppression (target protector) strategy can restore PAX6 protein levels. We show that miR-7 and miR-375 target specific sites within the Pax6 3' UTR in a mouse pancreatic β-insulinoma cell line. Tough decoys (Tuds) against miR-7 and miR-375 increase expression of a mouse Pax6 3' UTR luciferase reporter and increase PAX6 protein levels in these cells. Finally, we demonstrate that the shielding of the miR-7 binding site with a target protector restores PAX6 protein levels in the Pax6 heterozygous islets. The data presented here represent a proof of concept for RNA-based therapy for the progressive defects associated with aniridia and suggest the target protector approach may be a useful therapeutic strategy for other haploinsufficiency diseases., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)