Search Results (5)

Primary cilia play a significant role in influencing cell fate, including apoptosis in multiple cell types. In the lesional epidermis of vitiligo patients, a reduced number of ciliated cells was observed. Our study also revealed a downregulation of oral–facial digital syndrome type 1 (OFD1) in the affected skin of vitiligo patients. However, it remains unknown whether primary cilia are involved in the control of melanocyte apoptosis. While both intraflagellar transport 88 (IFT88) and retinitis pigmentosa GTPase regulator-interacting protein-1 like (RPGRIP1L) are associated with ciliogenesis in melanocytes, only the knockdown of OFD1, but not IFT88 and RPGRIP1L, resulted in increased melanocyte apoptosis. OFD1 knockdown led to a decrease in the expression of proteins involved in cell–extracellular matrix (ECM) interactions, including paxillin. The OFD1 amino acid residues 601-1012 interacted with paxillin, while the amino acid residues 1-601 were associated with ciliogenesis, suggesting that the OFD1 domains responsible for paxillin binding are distinct from those involved in ciliogenesis. OFD1 knockdown, but not IFT88 knockdown, inhibited melanocyte adhesion to the ECM, a defect that was restored by paxillin overexpression. In summary, our findings indicate that the downregulation of OFD1 induces melanocyte apoptosis, independent of any impairment in ciliogenesis, by reducing melanocyte adhesion to the ECM via paxillin. Full article

Maternal genetic effects (MGE) could affect meat quality traits such as intramuscular fat (IMF) and its fatty acid composition. However, it has been scarcely studied, especially in rabbits. The objectives of the present study were, first, to assess the importance of MGE on intramuscular fat and fatty acid composition by applying a Bayesian maternal animal model in two rabbit lines divergently selected for IMF. The second objective was to identify genomic regions and candidate genes of MGE that are associated with the traits of these offspring, using Bayesian methods in a Genome Wide Association Study (GWAS). Quantitative analyses were performed using data from 1982 rabbits, and 349 animals from the 9th generation and 76 dams of the 8th generation with 88,512 SNPs were used for the GWAS. The studied traits were IMF, saturated fatty acids (total SFA, C14:0; myristic acid, C16:0; palmitic acid and C18:0; stearic acid), monounsaturated fatty acids (total MUFA, C16:1n-7; palmitoleic acid and C18:1n-9; oleic acid), polyunsaturated fatty acids (total PUFA, C18:2n-6; linoleic acid, C18:3n-3; α-linolenic acid and C20:4n-6; arachidonic acid), MUFA/SFA and PUFA/SFA. The proportion of phenotypic variance explained by the maternal genetic effect ranged from 8 to 22% for IMF, depending on the model. For fatty acid composition, the proportion of phenotypic variance explained by maternal genetic effects varied from 10% (C18:0) to 46% (MUFA) in a model including both direct and additive maternal genetic effects, together with the common litter effect as a random variable. In particular, there were significant direct maternal genetic correlations for C16:0, C18:1n9, C18:2n6, SFA, MUFA, and PUFA with values ranging from −0.53 to −0.89. Relevant associated genomic regions were located on the rabbit chromosomes (OCU) OCU1, OCU5 and OCU19 containing some relevant candidates (TANC2, ACE, MAP3K3, TEX2, PRKCA, SH3GL2, CNTLN, RPGRIP1L and FTO) related to lipid metabolism, binding, and obesity. These regions explained about 1.2 to 13.9% of the total genomic variance of the traits studied. Our results showed an important maternal genetic effect on IMF and its fatty acid composition in rabbits and identified promising candidate genes associated with these traits. Full article

X-linked retinitis pigmentosa (XLRP) is frequently caused by mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene. A complex splicing process acts on the RPGR gene resulting in three major isoforms: RPGR^ex1-19, RPGR^ORF15 and RPGR^skip14/15. We characterized the widely expressed, alternatively spliced transcript RPGR^skip14/15 lacking exons 14 and 15. Using the CRISPR/eSpCas9 system, we generated HEK293T cell lines exclusively expressing the RPGR^skip14/15 transcript from the endogenous RPGR gene. RPGR^ex1-19 and RPGR^ORF15 were knocked out. Immunocytochemistry demonstrated that the RPGR^skip14/15 protein localizes along primary cilia, resembling the expression pattern of RPGR^ex1-19. The number of cilia-carrying cells was not affected by the absence of the RPGR^ex1-19 and RPGR^ORF15 isoforms. Co-immunoprecipitation assays demonstrated that both RPGR^ex1-19 and RPGR^skip14/15 interact with PDE6D, further supporting that RPGR^skip14/15 is associated with the protein networks along the primary cilium. Interestingly, interaction complexes with INPP5E or RPGRIP1L were only detectable with isoform RPGR^ex1-19, but not with RPGR^skip14/15, demonstrating distinct functional properties of the major RPGR isoforms in spite of their similar subcellular localization. Our findings lead to the conclusion that protein binding sites within RPGR are mediated through alternative splicing. A tissue-specific expression ratio between RPGR^skip14/15 and RPGR^ex1-19 seems required to regulate the ciliary concentration of RPGR interaction partners. Full article

Protein degradation is a pivotal process for eukaryotic development and homeostasis. The majority of proteins are degraded by the ubiquitin–proteasome system and by autophagy. Recent studies describe a crosstalk between these two main eukaryotic degradation systems which allows for establishing a kind of safety mechanism. If one of these degradation systems is hampered, the other compensates for this defect. The mechanism behind this crosstalk is poorly understood. Novel studies suggest that primary cilia, little cellular protrusions, are involved in the regulation of the crosstalk between the two degradation systems. In this review article, we summarise the current knowledge about the association between cilia, the ubiquitin–proteasome system and autophagy. Full article

The Hedgehog signalling pathway is evolutionarily highly conserved and essential for embryonic development of invertebrates and vertebrates. Consequently, impaired Hedgehog signalling results in very severe human diseases, ranging from holoprosencephaly to Pallister-Hall syndrome. Due to this great importance for human health, the focus of numerous research groups is placed on the investigation of the detailed mechanisms underlying Hedgehog signalling. Today, it is known that tiny cell protrusions, known as primary cilia, are necessary to mediate Hedgehog signalling in vertebrates. Although the Hedgehog pathway is one of the best studied signalling pathways, many questions remain. One of these questions is: How do primary cilia control Hedgehog signalling in vertebrates? Recently, it was shown that primary cilia regulate a special kind of proteasome which is essential for proper Hedgehog signalling. This review article will cover this novel cilia-proteasome association in embryonic Hedgehog signalling and discuss the possibilities provided by future investigations on this topic. Full article