scholarly journals Loss of Function of OsDCL1 Affects MicroRNA Accumulation and Causes Developmental Defects in Rice

2005 ◽  
Vol 139 (1) ◽  
pp. 296-305 ◽  
Author(s):  
Bin Liu ◽  
PingChuan Li ◽  
Xin Li ◽  
ChunYan Liu ◽  
ShouYun Cao ◽  
...  
Keyword(s):  
Loss Of Function ◽  
Developmental Defects

scholarly journals mRNA Surveillance Complex PELOTA-HBS1 Regulates Phosphoinositide-Dependent Protein Kinase1 and Plant Growth

2021 ◽  
Author(s):  
Wei Kong ◽  
Shutang Tan ◽  
Qing Zhao ◽  
De-Li Lin ◽  
Zhi-Hong Xu ◽  
...  
Keyword(s):  
Quality Control ◽  
Messenger Rna ◽  
Loss Of Function ◽  
Yeast Saccharomyces Cerevisiae ◽  
Developmental Defects ◽  
Mrna Surveillance ◽  
Dna Insertion ◽  
Dependent Protein ◽  
Heterodimeric Complex ◽  
Severe Growth

Abstract The quality control system for messenger RNA (mRNA) is fundamental for cellular activities in eukaryotes. To elucidate the molecular mechanism of 3’-Phosphoinositide-Dependent Protein Kinase1 (PDK1), a master regulator that is essential throughout eukaryotic growth and development, we employed a forward genetic approach to screen for suppressors of the loss-of-function T-DNA insertion double mutant pdk1.1 pdk1.2 in Arabidopsis thaliana. Notably, the severe growth attenuation of pdk1.1 pdk1.2 was rescued by sop21 (suppressor of pdk1.1 pdk1.2), which harbours a loss-of-function mutation in PELOTA1 (PEL1). PEL1 is a homologue of mammalian PELOTA and yeast (Saccharomyces cerevisiae) DOM34p, which each form a heterodimeric complex with the GTPase HBS1 (HSP70 SUBFAMILY B SUPPRESSOR1, also called SUPERKILLER PROTEIN7, SKI7), a protein that is responsible for ribosomal rescue and thereby assures the quality and fidelity of mRNA molecules during translation. Genetic analysis further revealed that a dysfunctional PEL1-HBS1 complex failed to degrade the T-DNA-disrupted PDK1 transcripts, which were truncated but functional, and thus rescued the growth and developmental defects of pdk1.1 pdk1.2. Our studies demonstrated the functionality of a homologous PELOTA-HBS1 complex and identified its essential regulatory role in plants, providing insights into the mechanism of mRNA quality control.

scholarly journals Inner Ear and Muscle Developmental Defects in Smpx-Deficient Zebrafish Embryos

2021 ◽  
Vol 22 (12) ◽  
pp. 6497
Author(s):  
Anna Ghilardi ◽  
Alberto Diana ◽  
Renato Bacchetta ◽  
Nadia Santo ◽  
Miriam Ascagni ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Inner Ear ◽  
Hair Cells ◽  
Muscle Fibers ◽  
Underlying Mechanism ◽  
Loss Of Function ◽  
Zebrafish Model ◽  
Developmental Defects ◽  
Inner Ear Development ◽  
Syndromic Hearing Loss

The last decade has witnessed the identification of several families affected by hereditary non-syndromic hearing loss (NSHL) caused by mutations in the SMPX gene and the loss of function has been suggested as the underlying mechanism. In the attempt to confirm this hypothesis we generated an Smpx-deficient zebrafish model, pointing out its crucial role in proper inner ear development. Indeed, a marked decrease in the number of kinocilia together with structural alterations of the stereocilia and the kinocilium itself in the hair cells of the inner ear were observed. We also report the impairment of the mechanotransduction by the hair cells, making SMPX a potential key player in the construction of the machinery necessary for sound detection. This wealth of evidence provides the first possible explanation for hearing loss in SMPX-mutated patients. Additionally, we observed a clear muscular phenotype consisting of the defective organization and functioning of muscle fibers, strongly suggesting a potential role for the protein in the development of muscle fibers. This piece of evidence highlights the need for more in-depth analyses in search for possible correlations between SMPX mutations and muscular disorders in humans, thus potentially turning this non-syndromic hearing loss-associated gene into the genetic cause of dysfunctions characterized by more than one symptom, making SMPX a novel syndromic gene.

scholarly journals Identification and validation of novel candidate risk genes in endocytic vesicular trafficking associated with esophageal atresia and tracheoesophageal fistulas

2021 ◽  
Author(s):  
Guojie Zhong ◽  
Priyanka Ahimaz ◽  
Nicole A. Edwards ◽  
Jacob J. Hagen ◽  
Christophe Faure ◽  
...  
Keyword(s):  
Genetic Variants ◽  
Congenital Anomalies ◽  
De Novo ◽  
Simulation Analysis ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Risk Genes ◽  
Significant Burden ◽  
Background Mutation Rate ◽  
Complex Cases

Esophageal atresias/tracheoesophageal fistulas (EA/TEF) are rare congenital anomalies caused by aberrant development of the foregut. Previous studies indicate that rare or de novo genetic variants significantly contribute to EA/TEF risk, and most individuals with EA/TEF do not have pathogenic genetic variants in established risk genes. To identify novel genetic contributions to EA/TEF, we performed whole genome sequencing of 185 trios (probands and parents) with EA/TEF, including 59 isolated and 126 complex cases with additional congenital anomalies and/or neurodevelopmental disorders. There was a significant burden of protein altering de novo coding variants in complex cases (p=3.3e-4), especially in genes that are intolerant of loss of function variants in the population. We performed simulation analysis of pathway enrichment based on background mutation rate and identified a number of pathways related to endocytosis and intracellular trafficking that as a group have a significant burden of protein altering de novo variants. We assessed 18 variants for disease causality using CRISPR-Cas9 mutagenesis in Xenopus and confirmed 13 with tracheoesophageal phenotypes. Our results implicate disruption of endosome-mediated epithelial remodeling as a potential mechanism of foregut developmental defects. This research may have implications for the mechanisms of other rare congenital anomalies.

scholarly journals Age-dependent degeneration of an identified adult leg motor neuron in a Drosophila SOD1 model of ALS

Biology Open ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. bio049692
Author(s):  
Anthony Agudelo ◽  
Victoria St. Amand ◽  
Lindsey Grissom ◽  
Danielle Lafond ◽  
Toni Achilli ◽  
...  
Keyword(s):  
Motor Neuron ◽  
Gene Replacement ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Age Related ◽  
Disease Mutations ◽  
Discs Large ◽  
Age Dependent ◽  
Motor Neuron Loss ◽  
Lateral Sclerosis

ABSTRACTMutations in superoxide dismutase 1 (SOD1) cause familial amyotrophic lateral sclerosis (ALS) in humans. ALS is a neurodegenerative disease characterized by progressive motor neuron loss leading to paralysis and inevitable death in affected individuals. Using a gene replacement strategy to introduce disease mutations into the orthologous Drosophila sod1 (dsod1) gene, here, we characterize changes at the neuromuscular junction using longer-lived dsod1 mutant adults. Homozygous dsod1H71Y/H71Y or dsod1null/null flies display progressive walking defects with paralysis of the third metathoracic leg. In dissected legs, we assessed age-dependent changes in a single identified motor neuron (MN-I2) innervating the tibia levitator muscle. At adult eclosion, MN-I2 of dsod1H71Y/H71Y or sod1null/null flies is patterned similar to wild-type flies indicating no readily apparent developmental defects. Over the course of 10 days post-eclosion, MN-I2 shows an overall reduction in arborization with bouton swelling and loss of the post-synaptic marker discs-large (dlg) in mutant dsod1 adults. In addition, increases in polyubiquitinated proteins correlate with the timing and extent of MN-I2 changes. Because similar phenotypes are observed between flies homozygous for either dsod1H71Y or dsod1null alleles, we conclude these NMJ changes are mainly associated with sod loss-of-function. Together these studies characterize age-related morphological and molecular changes associated with axonal retraction in a Drosophila model of ALS that recapitulate an important aspect of the human disease.This article has an associated First Person interview with the first author of the paper.

scholarly journals Mechanistic Insights into Axenfeld–Rieger Syndrome from Zebrafish foxc1 and pitx2 Mutants

2021 ◽  
Vol 22 (18) ◽  
pp. 10001
Author(s):  
Curtis R. French
Keyword(s):  
Transcription Factors ◽  
Developmental Disorders ◽  
Anterior Segment ◽  
Therapeutic Interventions ◽  
Loss Of Function ◽  
Cardiovascular Malformations ◽  
Developmental Defects ◽  
Rieger Syndrome ◽  
Function Models ◽  
Shed Light

Axenfeld–Rieger syndrome (ARS) encompasses a group of developmental disorders that affect the anterior segment of the eye, as well as systemic developmental defects in some patients. Malformation of the ocular anterior segment often leads to secondary glaucoma, while some patients also present with cardiovascular malformations, craniofacial and dental abnormalities and additional periumbilical skin. Genes that encode two transcription factors, FOXC1 and PITX2, account for almost half of known cases, while the genetic lesions in the remaining cases remain unresolved. Given the genetic similarity between zebrafish and humans, as well as robust antisense inhibition and gene editing technologies available for use in these animals, loss of function zebrafish models for ARS have been created and shed light on the mechanism(s) whereby mutations in these two transcription factors cause such a wide array of developmental phenotypes. This review summarizes the published phenotypes in zebrafish foxc1 and pitx2 loss of function models and discusses possible mechanisms that may be used to target pharmaceutical development and therapeutic interventions.

scholarly journals Isthmin1, a secreted signaling protein, acts downstream of diverse embryonic patterning centers in development

2020 ◽  
Author(s):  
Gokul Kesavan ◽  
Florian Raible ◽  
Mansi Gupta ◽  
Anja Machate ◽  
Dilara Yilmaz ◽  
...  
Keyword(s):  
Single Molecule ◽  
Gene Expression Pattern ◽  
Correlation Spectroscopy ◽  
Dependent Manner ◽  
Embryonic Patterning ◽  
Loss Of Function ◽  
Concentration Dependent Manner ◽  
Developmental Defects ◽  
Extracellular Signals

AbstractExtracellular signals play essential roles during embryonic patterning by providing positional information in a concentration-dependent manner, and many such signals, like Wnt, fibroblast growth factor (FGF), Hedgehog (Hh), and retinoic acid, act by being secreted into the extracellular space, thereby triggering receptor-mediated responses in other cells. Isthmin1 (ism1) is a secreted protein whose gene expression pattern coincides with that of early dorsal determinants, nodal ligand genes like sqt and cyc, and with fgf8 during various phases of zebrafish development. Ism1 functions in early embryonic patterning and development are poorly understood; however, it has recently been shown to interact with nodal pathway genes to control organ asymmetry in chicken. Here, we show that misexpression of ism1 deletion constructs disrupts embryonic patterning in zebrafish and exhibits genetic interactions with both Fgf and nodal signaling. Unlike Fgf and nodal pathway mutants, CRISPR/Cas9-engineered ism1 mutants did not show obvious developmental defects. Further, in vivo single molecule fluorescence correlation spectroscopy (FCCS) showed that Ism1 diffuses freely in the extra-cellular space, with a diffusion coefficient similar to that of Fgf8a; however, our measurements do not support direct molecular interactions between Ism1 and either nodal ligands or Fgf8a in the developing zebrafish embryo. Together, data from gain- and loss-of-function experiments suggest that zebrafish Ism1 plays a complex role in regulating extracellular signals during early embryonic development.

scholarly journals Efficient genome-wide first-generation phenotypic screening system in mice using thepiggyBactransposon

2019 ◽  
Vol 116 (37) ◽  
pp. 18507-18516 ◽  
Author(s):  
Hao Chang ◽  
Yukun Pan ◽  
Sean Landrette ◽  
Sheng Ding ◽  
Dong Yang ◽  
...  
Keyword(s):  
First Generation ◽  
Cranial Nerves ◽  
Model Organisms ◽  
Biological Traits ◽  
Screening System ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Genome Wide ◽  
A Genome ◽  
Milk Ingestion

Genome-wide phenotypic screens provide an unbiased way to identify genes involved in particular biological traits, and have been widely used in lower model organisms. However, cost and time have limited the utility of such screens to address biological and disease questions in mammals. Here we report a highly efficientpiggyBac(PB) transposon-based first-generation (F1) dominant screening system in mice that enables an individual investigator to conduct a genome-wide phenotypic screen within a year with fewer than 300 cages. ThePBscreening system uses visually trackable transposons to induce both gain- and loss-of-function mutations and generates genome-wide distributed new insertions in more than 55% of F1 progeny. Using this system, we successfully conducted a pilot F1 screen and identified 5 growth retardation mutations. One of these mutants, a Six1/4PB/+mutant, revealed a role in milk intake behavior. The mutant animals exhibit abnormalities in nipple recognition and milk ingestion, as well as developmental defects in cranial nerves V, IX, and X. ThisPBF1 screening system offers individual laboratories unprecedented opportunities to conduct affordable genome-wide phenotypic screens for deciphering the genetic basis of mammalian biology and disease pathogenesis.

scholarly journals Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Benjamin R. Thomson ◽  
Pan Liu ◽  
Tuncer Onay ◽  
Jing Du ◽  
Stuart W. Tompson ◽  
...  
Keyword(s):  
Aqueous Humor ◽  
Open Angle Glaucoma ◽  
Severe Disease ◽  
Congenital Glaucoma ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Aqueous Humor Outflow ◽  
Risk Alleles ◽  
Adult Mice ◽  
Outflow Pathway

AbstractPrimary congenital glaucoma (PCG) is a severe disease characterized by developmental defects in the trabecular meshwork (TM) and Schlemm’s canal (SC), comprising the conventional aqueous humor outflow pathway of the eye. Recently, heterozygous loss of function variants in TEK and ANGPT1 or compound variants in TEK/SVEP1 were identified in children with PCG. Moreover, common variants in ANGPT1and SVEP1 have been identified as risk alleles for primary open angle glaucoma (POAG) in GWAS studies. Here, we show tissue-specific deletion of Angpt1 or Svep1 from the TM causes PCG in mice with severe defects in the adjacent SC. Single-cell transcriptomic analysis of normal and glaucomatous Angpt1 deficient eyes allowed us to identify distinct TM and SC cell populations and discover additional TM-SC signaling pathways. Furthermore, confirming the importance of angiopoietin signaling in SC, delivery of a recombinant ANGPT1-mimetic promotes developmental SC expansion in healthy and Angpt1 deficient eyes, blunts intraocular pressure (IOP) elevation and RGC loss in a mouse model of PCG and lowers IOP in healthy adult mice. Our data highlight the central role of ANGPT1-TEK signaling and TM-SC crosstalk in IOP homeostasis and provide new candidates for SC-targeted glaucoma therapy.

scholarly journals Meiosis-Specific Cohesin Complexes Display Distinct and Essential Roles in Mitotic ESC Chromosomes

2021 ◽  
Author(s):  
Eui-Hwan Choi ◽  
Young Eun Koh ◽  
Seobin Yoon ◽  
Yoonsoo Hahn ◽  
Keun P Kim
Keyword(s):  
Embryonic Stem ◽  
Dependent Manner ◽  
Structured Illumination ◽  
Loss Of Function ◽  
Structured Illumination Microscopy ◽  
Developmental Defects ◽  
Chromatid Cohesion ◽  
Functional Analyses ◽  
Stalled Replication Forks ◽  
Mitosis And Meiosis

Cohesin is a chromosome-associated SMC-kleisin complex that mediates sister chromatid cohesion, recombination, and most chromosomal processes during mitosis and meiosis. Through high-resolution 3D-structured illumination microscopy and functional analyses, we report multiple biological processes associated with the meiosis-specific cohesin components, REC8 and STAG3, and the distinct loss of function of meiotic cohesin during the cell cycle of embryonic stem cells (ESCs). First, we show that REC8 is translocated into the nucleus in a STAG3-dependent manner. REC8/STAG3-containing cohesin regulates chromosome topological properties and specifically maintains centromeric cohesion. Second, REC8 and mitotic cohesin RAD21 are located at adjacent sites but predominantly at nonoverlapping sites on ESC chromosomes, implying that REC8 can function independent of RAD21 in ESCs. Third, knockdown of REC8-cohesin not only leads to higher rates of premature centromere separation and stalled replication forks, which can cause proliferation and developmental defects, but also enhances compaction of the chromosome structure by hyperloading of retinoblastoma protein-condensin complexes from prophase onward. We propose that the delicate balance between mitotic and meiotic cohesins may regulate ESC-specific chromosomal organization and mitotic program.

scholarly journals Comprehensive Analysis of LIN28A in Chinese Patients With Early Onset Parkinson’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiaojing Gu ◽  
Yanbing Hou ◽  
Yongping Chen ◽  
Ruwei Ou ◽  
Bei Cao ◽  
...  
Keyword(s):  
Early Onset ◽  
Chinese Patient ◽  
Chinese Patients ◽  
Loss Of Function ◽  
Developmental Defects ◽  
Functional Studies ◽  
Whole Exome ◽  
Increased Risk ◽  
Related Phenotype ◽  
Early Onset Parkinson’S Disease

A loss-of-function variant in Lin-28 Homolog A gene (LIN28A p. R192G, rs558060339) has been identified in two East Asian ancestry patients with early-onset PD (EOPD). Functional studies revealed that such a variant could lead to developmental defects and PD-related phenotype, and the phenotypes could be rescued after correction of the variant. The aim of the study was to screen the variants of LIN28A in Chinese patients with EOPD. A total of 682 EOPD patients were sequenced with whole exome sequencing and the coding and flanking region of LIN28A were analyzed. We identified a rare coding variant, p. P182L, of LIN28A in a Chinese patient with EOPD. Moreover, we also found a 3′-UTR polymorphism (rs4659441) to be associated with an increased risk for PD. However, our rare variant burden analysis did not support a role for LIN28A as a major causal gene for PD.

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