scholarly journals Growth- and stress-related defects associated to wall hypoacetylation are strigolactone-dependent

2018 ◽  
Author(s):  
Vicente Ramírez ◽  
Guangyan Xiong ◽  
Kiyoshi Mashiguchi ◽  
Shinjiro Yamaguchi ◽  
Markus Pauly
Keyword(s):  
Direct Effect ◽  
Freezing Tolerance ◽  
Suppressor Mutation ◽  
Compensatory Mechanism ◽  
Biosynthetic Gene ◽  
Loss Of Function ◽  
Strong Reduction ◽  
Branch Number ◽  
Biochemical Evidence ◽  
Constitutive Activation

ABSTRACTMutants affected in the Arabidopsis TBL29/ESK1 xylan O-acetyltransferase display a strong reduction in total wall O-acetylation accompanied by a dwarfed plant stature, collapsed xylem morphology, and enhanced freezing tolerance. A newly identified tbl29/esk1 suppressor mutation affects the biosynthesis of strigolactones (SL) due to the reduced expression of the MAX4 gene. Genetic and biochemical evidence suggests that blocking the biosynthesis of SL is sufficient to recover all developmental and stress-related defects associated with the TBL29/ESK1 loss of function without affecting its direct effect - reduced wall O-acetylation. Altered levels of the MAX4 SL biosynthetic gene, reduced branch number, and higher levels of methyl carlactonoate, an active SL, were also found in tbl29/esk1 plants consistent with a constitutive activation of the SL pathway. These results indicate that the reduction of O-acetyl substituents in xylan is not directly responsible for the observed tbl29/esk1 phenotypes. Alternatively, plants may perceive defects in the structure of wall polymers and/or wall architecture activating the SL hormonal pathway as a compensatory mechanism.

scholarly journals Constitutive activation of mTORC1 signaling induced by biallelic loss-of-function mutations in SZT2 underlies a discernible neurodevelopmental disease

PLoS ONE ◽  
2019 ◽  
Vol 14 (8) ◽  
pp. e0221482 ◽  
Author(s):  
Yuji Nakamura ◽  
Kohji Kato ◽  
Naomi Tsuchida ◽  
Naomichi Matsumoto ◽  
Yoshiyuki Takahashi ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Constitutive Activation ◽  
Neurodevelopmental Disease ◽  
Mtorc1 Signaling

scholarly journals Lack of the multidrug transporter MRP4/ABCC4 defines the PEL-negative blood group and impairs platelet aggregation

Blood ◽  
2020 ◽  
Vol 135 (6) ◽  
pp. 441-448 ◽  
Author(s):  
Slim Azouzi ◽  
Mahmoud Mikdar ◽  
Patricia Hermand ◽  
Emilie-Fleur Gautier ◽  
Virginie Salnot ◽  
...  
Keyword(s):  
Platelet Aggregation ◽  
Blood Group ◽  
K562 Cells ◽  
Large Deletion ◽  
Drug Dose ◽  
Compensatory Mechanism ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Whole Exome ◽  
Leukemia Treatment

Abstract The rare PEL-negative phenotype is one of the last blood groups with an unknown genetic basis. By combining whole-exome sequencing and comparative global proteomic investigations, we found a large deletion in the ABCC4/MRP4 gene encoding an ATP-binding cassette (ABC) transporter in PEL-negative individuals. The loss of PEL expression on ABCC4-CRISPR-Cas9 K562 cells and its overexpression in ABCC4-transfected cells provided evidence that ABCC4 is the gene underlying the PEL blood group antigen. Although ABCC4 is an important cyclic nucleotide exporter, red blood cells from ABCC4null/PEL-negative individuals exhibited a normal guanosine 3′,5′-cyclic monophosphate level, suggesting a compensatory mechanism by other erythroid ABC transporters. Interestingly, PEL-negative individuals showed an impaired platelet aggregation, confirming a role for ABCC4 in platelet function. Finally, we showed that loss-of-function mutations in the ABCC4 gene, associated with leukemia outcome, altered the expression of the PEL antigen. In addition to ABCC4 genotyping, PEL phenotyping could open a new way toward drug dose adjustment for leukemia treatment.

scholarly journals Canonical Wnt signaling exerts bidirectional control on choroid plexus epithelial development

2020 ◽  
Author(s):  
Arpan Parichha ◽  
Varun Suresh ◽  
Mallika Chatterjee ◽  
Aditya Kshirsagar ◽  
Lihi Ben-Reuven ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Choroid Plexus ◽  
Embryonic Stem ◽  
Mammalian Brain ◽  
Loss Of Function ◽  
Canonical Wnt Signaling ◽  
Constitutive Activation ◽  
Cortical Hem ◽  
And Function ◽  
Canonical Wnt

AbstractThe choroid plexus (CP) secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the CP epithelium (CPe) arises from the Wnt- and Bmp- expressing cortical hem. We examined the role of canonical Wnt signaling in CPe development and report that the mouse and human embryonic CPe expresses molecules in this pathway. Either loss of function or constitutive activation of β-catenin, a key mediator of canonical Wnt signaling, causes a profound disruption of mouse CPe development. Loss of β-catenin results in a dysmorphic CPe, while constitutive activation of β-catenin causes a loss of CPe identity and a transformation of this tissue to a hippocampal-like identity. Aspects of this phenomenon are recapitulated in human embryonic stem cell (hESC)-derived organoids. Our results indicate that canonical Wnt signaling is required in a precisely regulated manner for normal CP development in the mammalian brain.

scholarly journals CRISPR-Cas9-Mutated Pregnane X Receptor (pxr) Retains Pregnenolone-induced Expression of cyp3a65 in Zebrafish (Danio rerio) Larvae

2019 ◽  
Vol 174 (1) ◽  
pp. 51-62 ◽  
Author(s):  
Matthew C Salanga ◽  
Nadja R Brun ◽  
Rene D Francolini ◽  
John J Stegeman ◽  
Jared V Goldstone
Keyword(s):  
Gene Mutations ◽  
Pregnane X Receptor ◽  
Alternative Possibilities ◽  
Compensatory Mechanism ◽  
Loss Of Function ◽  
Coding Region ◽  
Compensatory Mechanisms ◽  
Transcriptional Responses ◽  
Test Species ◽  
Wide Range

Abstract Pregnane X receptor (PXR; NR1I2) is a nuclear receptor that regulates transcriptional responses to drug or xenobiotic exposure, including induction of CYP3A transcription, in many vertebrate species. PXR is activated by a wide range of ligands that differ across species, making functional studies on its role in the chemical defensome most relevant when approached in a species-specific manner. Knockout studies in mammals have shown a requirement for PXR in ligand-dependent activation of CYP3A expression or reporter gene activity. Morpholino knockdown of Pxr in zebrafish indicated a similar requirement. Here, we report on the generation of 2 zebrafish lines each carrying a heritable deletion in the pxr coding region, predicted to result in loss of a functional gene product. To our surprise, larvae homozygous for either of the pxr mutant alleles retain their ability to induce cyp3a65 mRNA expression following exposure to the established zebrafish Pxr ligand, pregnenolone. Thus, zebrafish carrying pxr alleles with deletions in either the DNA binding or the ligand-binding domains did not yield a loss-of-function phenotype, suggesting that a compensatory mechanism is responsible for cyp3a65 induction. Alternative possibilities are that Pxr is not required for the induction of selected genes, or that truncated yet functional mutant Pxr is sufficient for the downstream transcriptional effects. It is crucial that we develop a better understanding for the role of Pxr in this important biomedical test species. This study highlights the potential for compensatory mechanisms to avoid deleterious effects arising from gene mutations.

scholarly journals Genetic and physiological mechanisms of freezing tolerance in locally adapted populations of a winter annual

2019 ◽  
Author(s):  
Brian J. Sanderson ◽  
Sunchung Park ◽  
M. Inam Jameel ◽  
Joshua C. Kraft ◽  
Michael F. Thomashow ◽  
...  
Keyword(s):  
Local Adaptation ◽  
Freezing Tolerance ◽  
Adaptive Response ◽  
Sequence Polymorphism ◽  
Loss Of Function ◽  
Physiological Mechanisms ◽  
Naturally Occurring ◽  
Before And After ◽  
Winter Annual ◽  
Insight Into

ABSTRACTPremise of the studyDespite myriad examples of local adaptation, the phenotypes and genetic variants underlying such adaptive differentiation are seldom known. Recent work on freezing tolerance and local adaptation in ecotypes of Arabidopsis thaliana from Sweden and Italy provides the essential foundation for uncovering the genotype-phenotype-fitness map for an adaptive response to a key environmental stress.MethodsHere we examine the consequences of a naturally occurring loss of function (LOF) mutation in an Italian allele of the gene that encodes the transcription factor CBF2, which underlies a major freezing tolerance locus. We used four lines with a Swedish genetic background, each containing a LOF CBF2 allele. Two lines had introgression segments containing of the Italian CBF2 allele, and two were created using CRISPR-Cas9. We used a growth chamber experiment to quantify freezing tolerance and gene expression both before and after cold acclimation.Key resultsFreezing tolerance was greater in the Swedish (72%) compared to the Italian (11%) ecotype, and all four experimental CBF2 LOF lines had reduced freezing tolerance compared to the Swedish ecotype. Differential expression analyses identified ten genes for which all CBF2 LOF lines and the IT ecotype showed similar patterns of reduced cold responsive expression compared to the SW ecotype.ConclusionsWe identified ten genes that are at least partially regulated by CBF2 that may contribute to the differences in cold acclimated freezing tolerance between the Italian and Swedish ecotypes. These results provide novel insight into the molecular and physiological mechanisms connecting a naturally occurring sequence polymorphism to an adaptive response to freezing conditions.

scholarly journals Lysosomal perturbations in dopaminergic neurons derived from induced pluripotent stem cells with PARK2 mutation

2019 ◽  
Author(s):  
Justyna Okarmus ◽  
Helle Bogetofte ◽  
Sissel Ida Schmidt ◽  
Matias Ryding ◽  
Silvia Garcia Lopez ◽  
...  
Keyword(s):  
Dopaminergic Neurons ◽  
Induced Pluripotent Stem Cell ◽  
Autophagic Flux ◽  
Compensatory Mechanism ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Tem Analysis ◽  
Induced Pluripotent ◽  
And Function ◽  
The Impact

AbstractMutations in the PARK2 gene encoding parkin, an E3 ubiquitin ligase, are associated with autosomal recessive early-onset Parkinson’s disease (PD). While parkin has been implicated in the regulation of mitophagy and proteasomal degradation, the precise mechanism leading to neurodegeneration in both sporadic and familial PD upon parkin loss-of-function mutations remains unknown. Cultures of isogenic induced pluripotent stem cell (iPSC) lines with and without PARK2 knockout (KO) enable mechanistic studies of the effect of parkin deficiency in human dopaminergic neurons. In the present study, we used such cells to investigate the impact of PARK2 KO on the lysosomal compartment combining different approaches, such as mass spectrometry-based proteomics, electron microscopy (TEM) analysis and functional assays. We discovered a clear link between parkin deficiency and lysosomal alterations. PARK2 KO neurons exhibited a perturbed lysosomal morphology, displaying significantly enlarged and electron-lucent lysosomes as well as an increased total lysosomal content, which was exacerbated by mitochondrial stress. In addition, we found perturbed autophagic flux and decreased lysosomal enzyme activity suggesting an impairment of the autophagy-lysosomal pathway in parkin-deficient cells. Interestingly, activity of the GBA-encoded enzyme, β-glucocerebrosidase, was significantly increased suggesting the existence of a compensatory mechanism. In conclusion, our data provide a unique characterization of the morphology, content, and function of lysosomes in PARK2 KO neurons, thus revealing a new important connection between mitochondrial dysfunction and lysosomal dysregulation in PD pathogenesis.

scholarly journals Fgf3 is crucial for the generation of monoaminergic cerebrospinal fluid contacting cells in zebrafish

2018 ◽  
Author(s):  
Isabel Reuter ◽  
Jana Jäckels ◽  
Susanne Kneitz ◽  
Jochen Kuper ◽  
Klaus-Peter Lesch ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Signalling Pathway ◽  
Neuroendocrine Cells ◽  
Compensatory Mechanism ◽  
C Cells ◽  
Loss Of Function ◽  
Critical Importance ◽  
Summary Statement ◽  
Ets Domain ◽  
And Function

AbstractIn most vertebrates, including zebrafish, the hypothalamic serotonergic cerebrospinal fluid-contacting (CSF-c) cells constitute a prominent population. In contrast to the hindbrain serotonergic neurons, little is known about the development and function of these cells. Here, we identify Fibroblast growth factor (Fgf)3 as the main Fgf ligand controlling the ontogeny of serotonergic CSF-c cells. We show that fgf3 positively regulates the number of serotonergic CSF-c cells, as well as a subset of dopaminergic and neuroendocrine cells in the posterior hypothalamus. Further, expression of the ETS-domain transcription factor etv5b is downregulated after fgf3 impairment. Previous findings identified etv5b as critical for the proliferation of serotonergic progenitors in the hypothalamus, and therefore we now suggest that Fgf3 acts via etv5b during early development to ultimately control the number of mature serotonergic CSF-c cells. Moreover, our analysis of the developing hypothalamic transcriptome shows that the expression of fgf3 is upregulated upon fgf3 loss-of-function, suggesting activation of a self-compensatory mechanism. Together, these results highlight Fgf3 in a novel context as part of a signalling pathway of critical importance for hypothalamic development.Summary statementThis study highlights Fgf3 in a novel context where it is being part of a signalling pathway of critical importance for development of hypothalamic monoaminergic cells in zebrafish.

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