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The trypanosome flagellum as model for parasitology, cell biology and ciliopathies.

Cilia and flagella exhibit widely conserved structures and functions across species. In humans, defects in these organelles are responsible for diseases called ciliopathies and many model organisms are used to study them. In this review, we will discuss one of them, the parasite Trypanosoma brucei, which is particularly well-suited to investigate general aspects of cilia and flagella, such as construction or protein localisation. Its flagellum remains present throughout the cell cycle, offering the opportunity to monitor flagellum maintenance and assembly within the same cell. This model organism is very convenient for flagellum live imaging as well as expansion microscopy and ultrastructural studies, including focused ion beam - scanning electron microscopy (FIB-SEM). Efficient tools exist to manipulate the genome, including endogenous tagging, inducible expression system, RNA interference and CRISPR-Cas9 approaches. Here, we review original contributions from studies in trypanosome to our understanding of flagellum construction and intraflagellar transport, as well as the impact of gene mutations in some ciliopathies.

Flagella

The RNA splicing factor PRPF8 is required for left-right organiser cilia differentiation and determination of cardiac left-right asymmetry via regulation of Arl13b splicing.

Cilia function in the left-right organizer (LRO) is critical for determining internal organ asymmetry in vertebrates. To further understand the genetics of left-right asymmetry, we isolated a mouse mutant with laterality defects, l11Jus27, from a random mutagenesis screen. l11Jus27 mutants carry a missense mutation in the pre-mRNA processing factor, Prpf8. cephalophŏnus (cph) mutant zebrafish, carrying a protein truncating mutation in prpf8, phenocopy the laterality defects of l11Jus27 mutants. Prpf8 mutant mouse and fish embryos have increased expression of an alternative transcript encoding the cilium-associated protein, ARL13B, that lacks exon 9. In zebrafish, over-expression of the arl13b transcript lacking exon 9 perturbed cilium formation and caused laterality defects. The shorter ARL13B protein isoform lacked interactions with intraflagellar transport proteins. Our data suggest that PRPF8 plays a prominent role in LRO cilia by through the regulation of alternative splicing of ARL13B, thus uncovering a new mechanism for cilia-linked developmental defects.

ARL13B

Small noncoding RNAs and sperm nuclear basic proteins reflect the environmental impact on germ cells.

BACKGROUND: Molecular techniques can complement conventional spermiogram analyses to provide new information on the fertilizing potential of spermatozoa and to identify early alterations due to environmental pollution. METHODS: Here, we present a multilevel molecular profiling by small RNA sequencing and sperm nuclear basic protein analysis of male germ cells from 33 healthy young subjects residing in low and high-polluted areas. RESULTS: Although sperm motility and sperm concentration were comparable between samples from the two sites, those from the high-pollution area had a higher concentration of immature/immune cells, a lower protamine/histone ratio, a reduced ability of sperm nuclear basic proteins to protect DNA from oxidative damage, and an altered copper/zinc ratio in sperm. Sperm levels of 32 microRNAs involved in intraflagellar transport, oxidative stress response, and spermatogenesis were different between the two areas. In parallel, a decrease of Piwi-interacting RNA levels was observed in samples from the high-polluted area. CONCLUSIONS: This comprehensive analysis provides new insights into pollution-driven epigenetic alterations in sperm not detectable by spermiogram.

Male