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A novel meiosis-related lncRNA, Rbakdn, contributes to spermatogenesis by stabilizing Ptbp2

ABSTRACT: Spermatocyte meiosis is the cornerstone of mammalian production. Thousands of long noncoding RNAs (lncRNAs) have been reported to be functional in various cellular processes, but the function of lncRNAs in meiosis remains largely unknown. Here, we profiled lncRNAs in spermatocytes at stage I of meiosis and identified a testis-specific lncRNA, Rbakdn, as a vital regulator of meiosis. Rbakdn is dynamically expressed during meiosis I, and Rbakdn knockdown inhibits meiosis in vitro. Furthermore, Rbakdn knockdown in testes in mice by intratesticular injection disturbs meiosis, reduces testicular volume, and increases apoptosis of spermatocytes, resulting in vacuolation of the seminiferous tubules. Rbakdn can bind to Ptbp2, an RNA-binding protein that is important in the regulation of the alternative splicing of many genes in spermatogenesis. Rbakdn knockdown leads to a decrease in Ptbp2 through the ubiquitination degradation pathway, indicating that Rbakdn maintains the stability of Ptbp2. In conclusion, our study identified an lncRNA, Rbakdn, with a crucial role in meiosis.

ORGANISM(S): Mus musculus

PROVIDER: GSE183678 | GEO | 2021/11/04

REPOSITORIES: GEO

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Project description:The splicing regulator PTBP2 controls a program of embryonic splicing required for neuronal maturation. The splicing regulatory proteins PTBP1 and PTBP2 show distinct temporal expression profiles in the developing brain. Neuronal progenitor cells predominantly express PTBP1, whereas developing neurons express high levels of PTBP2, which are subsequently reduced late in neuronal maturation. We show here that PTBP2 and the program of splicing it controls are essential to proper neuronal maturation and survival. To investigate its in vivo function, we generated conditional PTBP2 null alleles in mice. Loss of PTBP2 in neuronal progenitor cells leads to neonatal death without gross defects in brain architecture. Mice with specific depletion of PTBP2 in the cortex and forebrain are viable. However over the first three postnatal weeks, when the normal cortex expands and develops mature circuits, the PTBP2 null cortices degenerate. We find that PTBP2-/- neurons cultured from embryonic brain show the same initial viability as wild type cells with proper early marker expression and neurite outgrowth. Strikingly, between 10 and 20 days in culture PTBP2 null neurons undergo a catastrophic failure to mature and die. To assess the target transcripts leading to these phenotypes, we examined the genomewide splicing changes in the PTBP2 null brains. This identified a large number of mis-regulated exons that share a temporal pattern of regulation; in the absence of PTBP2 many isoforms normally found in adults are precociously expressed in the developing brain. Transcripts following this pattern encode essential neuronal proteins affecting neurite growth, pre- and post-synaptic assembly, and synaptic transmission. Our results define a new genetic regulatory program essential for neuronal survival and maturation, where PTBP2 acts to temporarily repress expression of protein isoforms until the final maturation of the neuron. Mice carrying a conditional floxed PTBP2 allele of PTBP2 were crossed to mice carrying Cre recombinase driven by the nestin promoter. The resulting knockout mutant mouse brains were analyzed for changes in gene expression and alternative splicing. Knockout mice were compared to wildtype littermates. Whole mouse brain polyA plus RNA was isolated from three Nestin-cre knockout embryos at embryonic day 18 and compared to three wildtype littermates. RNA was converted to cDNA and used to probe Affymetrix MJAY splicing sensitive microarrays and analysed by Omniviewer to identify changes in splicing.

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A novel meiosis-related lncRNA, Rbakdn, contributes to spermatogenesis by stabilizing Ptbp2

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