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Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells.

ABSTRACT: Topoisomerase IIbeta (Top2b) is an enzyme that modulates DNA supercoiling by catalyzing the passage of DNA duplexes through one another. It is ubiquitously expressed in postmitotic cells and known to function during the development of neuromuscular junctions in the diaphragm and the proper formation of laminar structure in the cerebral cortex. However, due to the perinatal death phenotype of the traditional constitutive and brain-specific Top2b knockout mice, the precise in vivo function of Top2b, especially during postnatal neural development, remains to be determined. Using both the constitutive and retina-specific knockout mouse models, we showed that Top2b deficiency resulted in delayed neuronal differentiation, degeneration of the plexiform layers and outer segment of photoreceptors, as well as dramatic reduction in cell number in the retina. Genome-wide transcriptome analysis by RNA sequencing revealed that genes involved in neuronal survival and neural system development were preferentially affected in Top2b-deficient retinas. Collectively, our findings have indicated an important function of Top2b in proper development and the maintenance/survival of postmitotic neurons in the retina.

SUBMITTER: Li Y

PROVIDER: S-EPMC3925320 | biostudies-literature | 2014 Feb

REPOSITORIES: biostudies-literature

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Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells.

Li Ying Y Hao Hailing H Tzatzalos Evangeline E Lin Ren-Kuo RK Doh Sungtae S Liu Leroy F LF Lyu Yi Lisa YL Cai Li L

Biology open 20140215 2

Topoisomerase IIbeta (Top2b) is an enzyme that modulates DNA supercoiling by catalyzing the passage of DNA duplexes through one another. It is ubiquitously expressed in postmitotic cells and known to function during the development of neuromuscular junctions in the diaphragm and the proper formation of laminar structure in the cerebral cortex. However, due to the perinatal death phenotype of the traditional constitutive and brain-specific Top2b knockout mice, the precise in vivo function of Top2 ...[more]

PMID: 24463367

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Project description:Dosage compensation refers to the equalization of most X-linked gene products between males and females. In Drosophila, it is mediated by the MSL complex that preferentially associates with numerous sites on the X chromosome in somatic cells of males, and is responsible for an enhancement of the transcriptional rate of a substantial number of X-linked genes. Here we show that topoisomerase II (Topo II) is an integral part of the mechanistic basis of dosage compensation and we highlight a novel function for this enzyme. A widely accepted model of transcription postulates that the moving bubble generated by an RNA polymerase elongating complex induces positive DNA supercoiling in the region ahead of the complex and negative supercoiling in its wake. These transitory changes in supercoiling are resolved by the action of topoisomerases. We have investigated the role of Topo II in dosage compensation by RNAi-mediated depletion, and we have used chromatin immunoprecipitation to determine its genomic distribution and relative abundance on X-linked genes. Topo II is enriched on dosage compensated genes and this enrichment is independent from the approximate two-fold enhancement in transcription of these genes. We have demonstrated an RNA-dependent association of Topo II with MLE, the ATPase-helicase subunit of the MSL complex. Our results indicate a role for Topo II that is additional to and different from its function in restoring normal DNA superhelicity during the transcription process. We suggest that the enhanced level of Topo II alters the DNA supercoiling of compensated gene units to facilitate transcription and could provide a basis for the recent report that the MSL complex enhances transcription by increasing the rate of elongation of RNA polymerase II. Investigation of dosage compensated gene expression levels in S2 and S2 Topo II RNAi knockdown cells. mRNA was isolated from S2 cells and S2 cells with RNAi knockdown of Topo II. The mRNA was then converted to cDNA and hybridized to a NimbleGen D. melanogaster gene expression array. 2 replicates each.

Dataset Information

Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells.

Publications

Topoisomerase IIbeta is required for proper retinal development and survival of postmitotic cells.

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