scholarly journals Hydroxylated sphingolipid biosynthesis regulates photoreceptor apical domain morphogenesis

2020 ◽  
Vol 219 (12) ◽  
Author(s):  
Sarita Hebbar ◽  
Kai Schuhmann ◽  
Andrej Shevchenko ◽  
Elisabeth Knust
Keyword(s):  
Photoreceptor Cells ◽  
Domain Growth ◽  
Sphingolipid Metabolism ◽  
Shotgun Lipidomics ◽  
Growth Defects ◽  
Apical Domain ◽  
Apical Trafficking ◽  
Membrane Growth ◽  
Sphingolipid Biosynthesis

Apical domains of epithelial cells often undergo dramatic changes during morphogenesis to form specialized structures, such as microvilli. Here, we addressed the role of lipids during morphogenesis of the rhabdomere, the microvilli-based photosensitive organelle of Drosophila photoreceptor cells. Shotgun lipidomics analysis performed on mutant alleles of the polarity regulator crumbs, exhibiting varying rhabdomeric growth defects, revealed a correlation between increased abundance of hydroxylated sphingolipids and abnormal rhabdomeric growth. This could be attributed to an up-regulation of fatty acid hydroxylase transcription. Indeed, direct genetic perturbation of the hydroxylated sphingolipid metabolism modulated rhabdomere growth in a crumbs mutant background. One of the pathways targeted by sphingolipid metabolism turned out to be the secretory route of newly synthesized Rhodopsin, a major rhabdomeric protein. In particular, altered biosynthesis of hydroxylated sphingolipids impaired apical trafficking via Rab11, and thus apical membrane growth. The intersection of lipid metabolic pathways with apical domain growth provides a new facet to our understanding of apical growth during morphogenesis.

scholarly journals Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Víctor Faundes ◽  
Martin D. Jennings ◽  
Siobhan Crilly ◽  
Sarah Legraie ◽  
Sarah E. Withers ◽  
...  
Keyword(s):  
De Novo ◽  
Model Systems ◽  
Yeast Growth ◽  
Related Disorder ◽  
Optimal Position ◽  
Human Phenotype ◽  
Mendelian Disorder ◽  
Growth Defects ◽  
Polysome Profiling

AbstractThe structure of proline prevents it from adopting an optimal position for rapid protein synthesis. Poly-proline-tract (PPT) associated ribosomal stalling is resolved by highly conserved eIF5A, the only protein to contain the amino acid hypusine. We show that de novo heterozygous EIF5A variants cause a disorder characterized by variable combinations of developmental delay, microcephaly, micrognathia and dysmorphism. Yeast growth assays, polysome profiling, total/hypusinated eIF5A levels and PPT-reporters studies reveal that the variants impair eIF5A function, reduce eIF5A-ribosome interactions and impair the synthesis of PPT-containing proteins. Supplementation with 1 mM spermidine partially corrects the yeast growth defects, improves the polysome profiles and restores expression of PPT reporters. In zebrafish, knockdown eif5a partly recapitulates the human phenotype that can be rescued with 1 µM spermidine supplementation. In summary, we uncover the role of eIF5A in human development and disease, demonstrate the mechanistic complexity of EIF5A-related disorder and raise possibilities for its treatment.

scholarly journals The Role of Cdh1p in Maintaining Genomic Stability in Budding Yeast

Genetics ◽  
2003 ◽  
Vol 165 (2) ◽  
pp. 489-503 ◽  
Author(s):  
Karen E Ross ◽  
Orna Cohen-Fix
Keyword(s):  
Cell Cycle ◽  
Chromosome Segregation ◽  
Spindle Assembly Checkpoint ◽  
Chromosome Loss ◽  
Cyclin Dependent Kinase ◽  
Anaphase Promoting Complex ◽  
Growth Defects ◽  
Genes Encoding ◽  
Specificity Factor

Abstract Cdh1p, a substrate specificity factor for the cell cycle-regulated ubiquitin ligase, the anaphase-promoting complex/cyclosome (APC/C), promotes exit from mitosis by directing the degradation of a number of proteins, including the mitotic cyclins. Here we present evidence that Cdh1p activity at the M/G1 transition is important not only for mitotic exit but also for high-fidelity chromosome segregation in the subsequent cell cycle. CDH1 showed genetic interactions with MAD2 and PDS1, genes encoding components of the mitotic spindle assembly checkpoint that acts at metaphase to prevent premature chromosome segregation. Unlike cdh1Δ and mad2Δ single mutants, the mad2Δ cdh1Δ double mutant grew slowly and exhibited high rates of chromosome and plasmid loss. Simultaneous deletion of PDS1 and CDH1 caused extensive chromosome missegregation and cell death. Our data suggest that at least part of the chromosome loss can be attributed to kinetochore/spindle problems. Our data further suggest that Cdh1p and Sic1p, a Cdc28p/Clb inhibitor, have overlapping as well as nonoverlapping roles in ensuring proper chromosome segregation. The severe growth defects of both mad2Δ cdh1Δ and pds1Δ cdh1Δ strains were rescued by overexpressing Swe1p, a G2/M inhibitor of the cyclin-dependent kinase, Cdc28p/Clb. We propose that the failure to degrade cyclins at the end of mitosis leaves cdh1Δ mutant strains with abnormal Cdc28p/Clb activity that interferes with proper chromosome segregation.

scholarly journals Role of sphingolipid metabolism in neurodegeneration

2020 ◽  
Author(s):  
Manal Alaamery ◽  
Nour Albesher ◽  
Nora Aljawini ◽  
Moneera Alsuwailm ◽  
Salam Massadeh ◽  
...  
Keyword(s):  
Sphingolipid Metabolism

scholarly journals The cAMP-PKA Pathway Regulates Growth, Sexual and Asexual Differentiation, and Pathogenesis in Fusarium graminearum

2014 ◽  
Vol 27 (6) ◽  
pp. 557-566 ◽  
Author(s):  
Shuai Hu ◽  
Xiaoying Zhou ◽  
Xiaoying Gu ◽  
Shulin Cao ◽  
Chengfang Wang ◽  
...  
Keyword(s):  
Fusarium Graminearum ◽  
Vegetative Growth ◽  
Double Mutant ◽  
Elevated Temperatures ◽  
Hyphal Growth ◽  
Growth Defects ◽  
Plant Infection ◽  
Dependent Protein ◽  
Pka Pathway

Like many other filamentous ascomycetes, Fusarium graminearum contains two genes named CPK1 and CPK2 that encode the catalytic subunits of cyclic AMP (cAMP)-dependent protein kinase A (PKA). To determine the role of cAMP signaling in pathogenesis and development in F. graminearum, we functionally characterized these two genes. In addition, we generated and characterized the cpk1 cpk2 double and fac1 adenylate cyclase gene deletion mutants. The cpk1 mutant was significantly reduced in vegetative growth, conidiation, and deoxynivalenol production but it had increased tolerance to elevated temperatures. It was defective in the production of penetration branches on plant surfaces, colonization of wheat rachises, and spreading in flowering wheat heads. Deletion of CPK1 had no effect on perithecium development but the cpk1 mutant was defective in ascospore maturation and releasing. In contrast, the cpk2 mutant had no detectable phenotypes, suggesting that CPK2 contributes minimally to PKA activities in F. graminearum. Nevertheless, the cpk1 cpk2 double mutant had more severe defects in vegetative growth and rarely produced morphologically abnormal conidia. The double mutant, unlike the cpk1 or cpk2 mutant, was nonpathogenic and failed to form perithecia on self-mating plates. Therefore, CPK1 and CPK2 must have overlapping functions in vegetative growth, differentiation, and plant infection in F. graminearum. The fac1 mutant was also nonpathogenic and had growth defects similar to those of the cpk1 cpk2 mutant. However, deletion of FAC1 had no effect on conidium morphology. These results indicated that CPK1 is the major PKA catalytic subunit gene and that the cAMP-PKA pathway plays critical roles in hyphal growth, conidiation, ascosporogenesis, and plant infection in F. graminearum.

scholarly journals A bipolar role of the transcription factor ERG for cnidarian germ layer formation and apical domain patterning

2017 ◽  
Vol 430 (2) ◽  
pp. 346-361 ◽  
Author(s):  
Aldine R. Amiel ◽  
Hereroa Johnston ◽  
Taylor Chock ◽  
Paul Dahlin ◽  
Marta Iglesias ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Germ Layer ◽  
Layer Formation ◽  
Apical Domain ◽  
Germ Layer Formation

scholarly journals Role of Spastin in Apical Domain Control along the Rhabdomere Elongation in Drosophila Photoreceptor

PLoS ONE ◽  
2010 ◽  
Vol 5 (3) ◽  
pp. e9480 ◽  
Author(s):  
Geng Chen ◽  
Garrett P. League ◽  
Sang-Chul Nam
Keyword(s):  
Apical Domain ◽  
Drosophila Photoreceptor

scholarly journals The Sphingolipid Asset Is Altered in the Nigrostriatal System of Mice Models of Parkinson’s Disease

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 93
Author(s):  
Victor Blokhin ◽  
Maria Shupik ◽  
Ulyana Gutner ◽  
Ekaterina Pavlova ◽  
Albert T. Lebedev ◽  
...  
Keyword(s):  
Gene Expression ◽  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sphingolipid Metabolism ◽  
Nigrostriatal System ◽  
Dopaminergic Cell ◽  
Metabolism Enzymes ◽  
Clinical Stages ◽  
Sphingosine 1 Phosphate

Parkinson’s disease (PD) is a neurodegenerative disease incurable due to late diagnosis and treatment. Therefore, one of the priorities of neurology is to study the mechanisms of PD pathogenesis at the preclinical and early clinical stages. Given the important role of sphingolipids in the pathogenesis of neurodegenerative diseases, we aimed to analyze the gene expression of key sphingolipid metabolism enzymes (ASAH1, ASAH2, CERS1, CERS3, CERS5, GBA1, SMPD1, SMPD2, UGCG) and the content of 32 sphingolipids (subspecies of ceramides, sphingomyelins, monohexosylceramides and sphinganine, sphingosine, and sphingosine-1-phosphate) in the nigrostriatal system in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models of the preclinical and clinical stages of PD. It has been shown that in PD models, the expression of five of the nine studied genes (CERS1, CERS5, ASAH1, ASAH2, and GBA1) increases but only in the substantia nigra (SN) containing dopaminergic cell bodies. Changes in the expression of enzyme genes were accompanied by an increase in the content of 7 of the 32 studied sphingolipids. Such findings suggest these genes as attractive candidates for diagnostic purposes for preclinical and clinical stages of PD.

Regulation of de novo sphingolipid biosynthesis and the toxic consequences of its disruption

2001 ◽  
Vol 29 (6) ◽  
pp. 831-835 ◽  
Author(s):  
S. C. Linn ◽  
H. S. Kim ◽  
E. M. Keane ◽  
L. M. Andras ◽  
E. Wang ◽  
...  
Keyword(s):  
De Novo ◽  
Uv Light ◽  
Wide Spectrum ◽  
Sphingolipid Metabolism ◽  
Intrinsic Activity ◽  
Type I ◽  
Serine Palmitoyltransferase ◽  
Post Translational Modification ◽  
Sphingolipid Biosynthesis ◽  
Complex Sphingolipids

Complex sphingolipids are ‘built’ on highly bio-active backbones (sphingoid bases and ceramides) that can cause cell death when the amounts are elevated by turnover of complex sphingolipids, disruption of normal sphingolipid metabolism, or over-induction of sphingolipid biosynthesis de novo. Under normal conditions, it appears that the bioactive intermediates of this pathway (3-keto-sphinganine, sphinganine and ceramides) are kept at relatively low levels. Both the intrinsic activity of serine palmitoyltransferase (SPT) and the availability of its substrates (especially palmitoyl-CoA) can have toxic consequences for cells by increasing the production of cytotoxic intermediates. Recent work has also revealed that diverse agonists and stresses (cytokines, UV light, glucocorticoids, heat shock and toxic compounds) modulate SPT activity by induction of SPTLC2 gene transcription and/or post-translational modification. Mutation of the SPTLC1 component of SPT has also been shown to cause hereditary sensory neuropathy type I, possibly via aberrant oversynthesis of sphingolipids. Another key step of the pathway is the acylation of sphinganine (and sphingosine in the recycling pathway) by ceramide synthase, and up-regulation of this enzyme (or its inhibition to cause accumulation of sphinganine) can also be toxic for cells. Since it appears that most, if not all, tissues synthesize sphingolipids de novo, it may not be surprising that disruption of this pathway has been implicated in a wide spectrum of disease.

The role of splicing factors in retinitis pigmentosa: links to cilia

2021 ◽  
Author(s):  
Dale W. Maxwell ◽  
Raymond T. O'Keefe ◽  
Sudipto Roy ◽  
Kathryn E. Hentges
Keyword(s):  
Retinitis Pigmentosa ◽  
Primary Cilium ◽  
Photoreceptor Cells ◽  
Genetic Mutations ◽  
Splicing Factors ◽  
Sequence Variants ◽  
Biological Functions ◽  
Progressive Degeneration

Cilia are critical to numerous biological functions, both in development and everyday homeostatic processes. Diseases arising from genetic mutations that cause cilia dysfunction are termed ciliopathies. Several ubiquitously expressed splicing factors have been implicated in the condition Retinitis Pigmentosa (RP), a group of diseases characterised by the progressive degeneration of the retina. In many types of RP the disease affects the modified primary cilium of the photoreceptor cells and thus, these types of RP are considered ciliopathies. Here, we discuss sequence variants found within a number of these splicing factors, the resulting phenotypes, and the mechanisms underpinning disease pathology. Additionally, we discuss recent evidence investigating why RP patients with mutations in globally expressed splicing factors present with retina-specific phenotypes.

scholarly journals Feeding Stimulates Sphingosine-1-Phosphate Mobilization in Mouse Hypothalamus

2019 ◽  
Vol 20 (16) ◽  
pp. 4008
Author(s):  
Valentina Vozella ◽  
Natalia Realini ◽  
Alessandra Misto ◽  
Daniele Piomelli
Keyword(s):  
De Novo ◽  
Sphingolipid Metabolism ◽  
Rt Pcr ◽  
Liquid Chromatography Tandem Mass ◽  
Sphingosine 1 Phosphate ◽  
Phosphate Mobilization ◽  
S1p Receptor ◽  
Free Feeding ◽  
G Protein Coupled ◽  
Sphingolipid Biosynthesis

Previous studies have shown that the sphingolipid-derived mediator sphingosine-1-phosphate (S1P) reduces food intake by activating G protein-coupled S1P receptor-1 (S1PR1) in the hypothalamus. Here, we examined whether feeding regulates hypothalamic mobilization of S1P and other sphingolipid-derived messengers. We prepared lipid extracts from the hypothalamus of C57Bl6/J male mice subjected to one of four conditions: free feeding, 12 h fasting, and 1 h or 6 h refeeding. Liquid chromatography/tandem mass spectrometry was used to quantify various sphingolipid species, including sphinganine (SA), sphingosine (SO), and their bioactive derivatives SA-1-phosphate (SA1P) and S1P. In parallel experiments, transcription of S1PR1 (encoded in mice by the S1pr1 gene) and of key genes of sphingolipid metabolism (Sptlc2, Lass1, Sphk1, Sphk2) was measured by RT-PCR. Feeding increased levels of S1P (in pmol-mg−1 of wet tissue) and SA1P. This response was accompanied by parallel changes in SA and dihydroceramide (d18:0/18:0), and was partially (SA1P) or completely (S1P) reversed by fasting. No such effects were observed with other sphingolipid species targeted by our analysis. Feeding also increased transcription of Sptlc2, Lass1, Sphk2, and S1pr1. Feeding stimulates mobilization of endogenous S1PR1 agonists S1P and SA1P in mouse hypothalamus, via a mechanism that involves transcriptional up-regulation of de novo sphingolipid biosynthesis. The results support a role for sphingolipid-mediated signaling in the central control of energy balance.

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