Mechanisms of impaired lung development and ciliation in Mannosidase-1-alpha-2 (Man1a2) mutants
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA721861 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14235900_1.fastq.gz | Fastqsanger.gz | |||
| SRR14235900_2.fastq.gz | Fastqsanger.gz | |||
| SRR14235901_1.fastq.gz | Fastqsanger.gz | |||
| SRR14235901_2.fastq.gz | Fastqsanger.gz | |||
| SRR14235886_1.fastq.gz | Fastqsanger.gz |
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Project description:Ciliary defects cause heterogenous phenotypes related to mutation burden which lead to impaired development. A previously reported homozygous deletion in the Man1a2 gene causes lethal respiratory failure in newborn pups and decreased lung ciliation compared with wild type (WT) pups. The effects of heterozygous mutation, and the potential for rescue are not known. Purpose: We hypothesized that survival and lung ciliation a) would decrease progressively in Man1a2 +/- heterozygous and Man1a2 -/- null newborn pups compared with WT, and b) could be enhanced by gestational treatment with N-Acetyl-cysteine (NAC), an antioxidant. Methods: Man1a2 +/- adult mice were fed NAC or placebo from a week before breeding through gestation. Survival of newborn pups was monitored for 24 hours. Lungs, liver and tails were harvested for morphology, genotyping and transcriptional profiling. Results: Survival (p=0.0001, Kaplan-Meier) and percent lung ciliation (p=0.0001, ANOVA) measured by frequency of Arl13b+ respiratory epithelial cells decreased progressively, as hypothesized. Compared with placebo, gestational NAC treatment enhanced a) lung ciliation in pups with each genotype, b) survival in heterozygous pups (p=0.017) but not in WT or null pups. Whole transcriptome of lung but not liver demonstrated patterns of up- and down-regulated genes that were identical in living heterozygous and WT pups, and completely opposite to those in dead heterozygous and null pups. Systems biology analysis enabled reconstruction of protein interaction networks that yielded functionally relevant modules and their interactions. In these networks, the mutant Man1a2 enzyme contributes to abnormal synthesis of proteins essential for lung development. The associated unfolded protein, hypoxic and oxidative stress responses can be mitigated with NAC. Comparisons with the developing human fetal lung transcriptome show that NAC likely restores normal vascular and epithelial tube morphogenesis in Man1a2 mutant mice. Conclusions: Survival and lung ciliation in the Man1a2 mutant mouse, and its improvement with N-Acetyl cysteine is genotype-dependent. NAC-mediated rescue depends on the central role for oxidative and hypoxic stress in regulating ciliary function and organogenesis during development
2021-08-11 | GSE172035 | GEO
Project description:BackgroundCiliary defects cause heterogenous phenotypes related to mutation burden which lead to impaired development. A previously reported homozygous deletion in the Man1a2 gene causes lethal respiratory failure in newborn pups and decreased lung ciliation compared with wild type (WT) pups. The effects of heterozygous mutation, and the potential for rescue are not known.PurposeWe hypothesized that survival and lung ciliation, (a) would decrease progressively in Man1a2 +/- heterozygous and Man1a2 -/- null newborn pups compared with WT, and (b) could be enhanced by gestational treatment with N-Acetyl-cysteine (NAC), an antioxidant.MethodsMan1a2+/- adult mice were fed NAC or placebo from a week before breeding through gestation. Survival of newborn pups was monitored for 24 h. Lungs, liver and tails were harvested for morphology, genotyping, and transcriptional profiling.ResultsSurvival (p = 0.0001, Kaplan-Meier) and percent lung ciliation (p = 0.0001, ANOVA) measured by frequency of Arl13b+ respiratory epithelial cells decreased progressively, as hypothesized. Compared with placebo, gestational NAC treatment enhanced (a) lung ciliation in pups with each genotype, (b) survival in heterozygous pups (p = 0.017) but not in WT or null pups. Whole transcriptome of lung but not liver demonstrated patterns of up- and down-regulated genes that were identical in living heterozygous and WT pups, and completely opposite to those in dead heterozygous and null pups. Systems biology analysis enabled reconstruction of protein interaction networks that yielded functionally relevant modules and their interactions. In these networks, the mutant Man1a2 enzyme contributes to abnormal synthesis of proteins essential for lung development. The associated unfolded protein, hypoxic and oxidative stress responses can be mitigated with NAC. Comparisons with the developing human fetal lung transcriptome show that NAC likely restores normal vascular and epithelial tube morphogenesis in Man1a2 mutant mice.ConclusionSurvival and lung ciliation in the Man1a2 mutant mouse, and its improvement with N-Acetyl cysteine is genotype-dependent. NAC-mediated rescue depends on the central role for oxidative and hypoxic stress in regulating ciliary function and organogenesis during development.
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Project description:ra09-03_sgs - mutants versus wt - Identification of new genes regulated by SGS1 and SGS6/UBP5 (two genes involved in PTGS) by analysis of the transcriptomes of sgs1 and sgs6 mutants compared to wild-type plants in the shoots of seedlings. The comparison between the transcriptomes of sgs3, chr11, chr17 simple mutants impaired differently in PTGS and development (juvenile-to-adult transition and bolting), and the transcriptomes of the sgs3 chr11, sgs3 chr17 double mutants showed additive effects on development (juvenile-to-adult transition and bolting), which allows a better understanding of the genetic link existing between SGS3 and its potential partners, CHR11 (which interacts with SGS3 in a two-hybrid assay and BiFC) and CHR17, 2 homologous proteins of the SWI/SNF2 family. Transcriptome comparison between mutants and wild-type plants L1 in the shoots of seedlings. 14 dye-swaps - gene knock-in (transgenic).
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