Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 4 de 4
Filter
Add more filters










Database
Language
Publication year range
1.
Genetics ; 227(3)2024 Jul 08.
Article in English | MEDLINE | ID: mdl-38797870

ABSTRACT

The major loci for the large primary ribosomal RNA (rRNA) genes (35S rRNAs) exist as hundreds to thousands of tandem repeats in all organisms and dozens to hundreds in Drosophila. The highly repetitive nature of the ribosomal DNA (rDNA) makes it intrinsically unstable, and many conditions arise from the reduction in or magnification of copy number, but the conditions under which it does so remain unknown. By targeted DNA damage to the rDNA of the Y chromosome, we created and investigated a series of rDNA alleles. We found that complete loss of rDNA leads to lethality after the completion of embryogenesis, blocking larval molting and metamorphosis. We find that the resident retrotransposons-R1 and R2-are regulated by active rDNA such that reduction in copy number derepresses these elements. Their expression is highest during the early first instar, when loss of rDNA is lethal. Regulation of R1 and R2 may be related to their structural arrangement within the rDNA, as we find they are clustered in the flanks of the nucleolus organizing region (NOR; the cytological appearance of the rDNA). We assessed the complex nucleolar dominance relationship between X- and Y-linked rDNA using a histone H3.3-GFP reporter construct and incorporation at the NOR and found that dominance is controlled by rDNA copy number as at high multiplicity the Y-linked array is dominant, but at low multiplicity the X-linked array becomes derepressed. Finally, we found that multiple conditions that disrupt nucleolar dominance lead to increased rDNA magnification, suggesting that the phenomena of dominance and magnification are related, and a single mechanism may underlie and unify these two longstanding observations in Drosophila.


Subject(s)
Alleles , DNA, Ribosomal , Animals , DNA, Ribosomal/genetics , Drosophila melanogaster/genetics , Drosophila melanogaster/growth & development , Retroelements/genetics , Nucleolus Organizer Region/genetics , Male , Sequence Deletion
2.
Semin Cell Dev Biol ; 136: 38-48, 2023 02 28.
Article in English | MEDLINE | ID: mdl-35595601

ABSTRACT

The ribosomal DNA (rDNA) in Drosophila is found as two additive clusters of individual 35 S cistrons. The multiplicity of rDNA is essential to assure proper translational demands, but the nature of the tandem arrays expose them to copy number variation within and between populations. Here, we discuss means by which a cell responds to insufficient rDNA copy number, including a historical view of rDNA magnification whose mechanism was inferred some 35 years ago. Recent work has revealed that multiple conditions may also result in rDNA loss, in response to which rDNA magnification may have evolved. We discuss potential models for the mechanism of magnification, and evaluate possible consequences of rDNA copy number variation.


Subject(s)
DNA Copy Number Variations , Drosophila melanogaster , Animals , DNA, Ribosomal/genetics , DNA Copy Number Variations/genetics , Drosophila melanogaster/genetics , Drosophila/genetics , Ribosomes
3.
PLoS Biol ; 18(12): e3001001, 2020 12.
Article in English | MEDLINE | ID: mdl-33362208

ABSTRACT

Histone variants expand chromatin functions in eukaryote genomes. H2A.B genes are testis-expressed short histone H2A variants that arose in placental mammals. Their biological functions remain largely unknown. To investigate their function, we generated a knockout (KO) model that disrupts all 3 H2A.B genes in mice. We show that H2A.B KO males have globally altered chromatin structure in postmeiotic germ cells. Yet, they do not show impaired spermatogenesis or testis function. Instead, we find that H2A.B plays a crucial role postfertilization. Crosses between H2A.B KO males and females yield embryos with lower viability and reduced size. Using a series of genetic crosses that separate parental and zygotic contributions, we show that the H2A.B status of both the father and mother, but not of the zygote, affects embryonic viability and growth during gestation. We conclude that H2A.B is a novel parental-effect gene, establishing a role for short H2A histone variants in mammalian development. We posit that parental antagonism over embryonic growth drove the origin and ongoing diversification of short histone H2A variants in placental mammals.


Subject(s)
Embryonic Development/genetics , Histones/genetics , Animals , Chromatin/genetics , Female , Gene Expression Regulation, Developmental/genetics , Genetic Variation , Genome/genetics , Histones/metabolism , Infertility, Male/genetics , Male , Mice/embryology , Mice, Knockout , Testis/embryology , Testis/metabolism
4.
Elife ; 82019 10 30.
Article in English | MEDLINE | ID: mdl-31663851

ABSTRACT

The autosomal dominant neuronal ceroid lipofuscinoses (NCL) CLN4 is caused by mutations in the synaptic vesicle (SV) protein CSPα. We developed animal models of CLN4 by expressing CLN4 mutant human CSPα (hCSPα) in Drosophila neurons. Similar to patients, CLN4 mutations induced excessive oligomerization of hCSPα and premature lethality in a dose-dependent manner. Instead of being localized to SVs, most CLN4 mutant hCSPα accumulated abnormally, and co-localized with ubiquitinated proteins and the prelysosomal markers HRS and LAMP1. Ultrastructural examination revealed frequent abnormal membrane structures in axons and neuronal somata. The lethality, oligomerization and prelysosomal accumulation induced by CLN4 mutations was attenuated by reducing endogenous wild type (WT) dCSP levels and enhanced by increasing WT levels. Furthermore, reducing the gene dosage of Hsc70 also attenuated CLN4 phenotypes. Taken together, we suggest that CLN4 alleles resemble dominant hypermorphic gain of function mutations that drive excessive oligomerization and impair membrane trafficking.


Subject(s)
Drosophila melanogaster/genetics , Gain of Function Mutation , Neuronal Ceroid-Lipofuscinoses/genetics , Neurons/metabolism , Animals , Animals, Genetically Modified , Disease Models, Animal , Drosophila melanogaster/metabolism , HSP40 Heat-Shock Proteins/genetics , HSP40 Heat-Shock Proteins/metabolism , Humans , Lysosomal-Associated Membrane Protein 1/genetics , Lysosomal-Associated Membrane Protein 1/metabolism , Lysosomes/metabolism , Membrane Proteins/genetics , Membrane Proteins/metabolism , Microscopy, Electron, Transmission , Neuronal Ceroid-Lipofuscinoses/metabolism , Neurons/ultrastructure , Synaptic Vesicles/metabolism , Ubiquitinated Proteins/genetics , Ubiquitinated Proteins/metabolism
SELECTION OF CITATIONS
SEARCH DETAIL
...