The Wnt/Wg pathway controls myriads of biological phenomena throughout the development and adult life of all organisms across the phyla. Thus, an aberrant Wnt signaling is associated with a wide range of pathologies in humans. Tight regulation of Wnt/Wg signaling is required to maintain proper cellular homeostasis.
View Article and Find Full Text PDFThe Notch pathway is an evolutionarily conserved signaling system that is intricately regulated at multiple levels and it influences different aspects of development. In an effort to identify novel components involved in Notch signaling and its regulation, we carried out protein interaction screens which identified non-muscle myosin II Zipper (Zip) as an interacting partner of Notch. Physical interaction between Notch and Zip was further validated by co-immunoprecipitation studies.
View Article and Find Full Text PDFX-linked retinoschisis (XLR) is a rare medical condition that involves in the splitting of neurosensory layers and the impairment of vision in the retina. In majority of the XLR cases, pathogenic variants in Retinoschisin 1 (RS1) gene have been implicated in males with an early age of onset during early childhood. In the present study, we have recruited two North Indian families having multiple affected male members, who were diagnosed with XLR.
View Article and Find Full Text PDFNotch pathway is an evolutionarily conserved signalling system that operates to influence an astonishing array of cell fate decisions in different developmental contexts. Notch signalling plays important roles in many developmental processes, making it difficult to name a tissue or a developing organ that does not depend on Notch function at one stage or another. Thus, dysregulation of Notch signalling is associated with many developmental defects and various pathological conditions, including cancer.
View Article and Find Full Text PDFA-kinase anchoring protein (AKAP) comprises a family of scaffold proteins, which decides the subcellular localisation of a combination of signalling molecules. Spoonbill (Spoon) is a putative A-kinase anchoring protein in Drosophila. We have earlier reported that Spoon suppresses ribonuclear foci formed by trinucleotide repeat expanded transcripts associated with Spinocerebellar Ataxia 8 neurodegeneration in Drosophila.
View Article and Find Full Text PDFDeltex (Dx) is a context-dependent regulator of Notch signaling that can act in a non-canonical fashion by facilitating the endocytosis of the Notch receptor. In an RNAi-based modifier screen of kinases and phosphatases, we identified Thickveins (Tkv), the receptor of Decapentaplegic (Dpp), as one of the interactors of Dx. Dpp, a Drosophila homolog of TGF-β and bone morphogenetic proteins, acts as a morphogen to specify cell fate along the anterior-posterior axis of the wing.
View Article and Find Full Text PDFAmyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) primarily affect the motor and frontotemporal areas of the brain, respectively. These disorders share clinical, genetic, and pathological similarities, and approximately 10-15% of ALS-FTD cases are considered to be multisystemic. ALS-FTD overlaps have been linked to families carrying an expansion in the intron of C9orf72 along with inclusions of TDP-43 in the brain.
View Article and Find Full Text PDFNotch signaling regulates an array of developmental decisions and has been implicated in a multitude of diseases, including cancer over the past a few decades. The simplicity and versatility of the Notch pathway in Drosophila make it an ardent system to study Notch biology, its regulation, and functions. In this chapter, we highlight the use of two powerful techniques, namely, FLP/FRT and MARCM in the study of Notch signaling.
View Article and Find Full Text PDFWe report on the genetic analysis of a north Indian family affected with Stargardt-like juvenile macular dystrophy. Considering an autosomal recessive inheritance of macular dystrophy in the recruited family, whole exome sequencing was employed in two affected siblings and their mother. We have identified a novel splice-site variant NC_000003.
View Article and Find Full Text PDFMaheshvara (mahe), an RNA helicase that is widely conserved across taxa, regulates Notch signaling and neuronal development in Drosophila. In order to identify novel components regulated by mahe, transcriptome profiling of ectopic mahe was carried out and this revealed striking upregulation of JAK/STAT pathway components like upd1, upd2, upd3, and socs36E. Further, significant downregulation of the pathway components in mahe loss-of-function mutant as well as upon lowering the level of mahe by RNAi, supported and strengthened our transcriptome data.
View Article and Find Full Text PDFNotch signaling is an evolutionarily conserved pathway that is widely used for multiple cellular events during development. Activation of the Notch pathway occurs when the ligand from a neighboring cell binds to the Notch receptor and induces cleavage of the intracellular domain of Notch, which further translocates into the nucleus to activate its downstream genes. The involvement of the Notch pathway in diverse biological events is possible due to the complexity in its regulation.
View Article and Find Full Text PDFToll pathway is the center for the function of immune system in both Drosophila and mammals. Toll pathway in Drosophila gets activated upon binding of the ligand Spätzle to the receptor, Toll, triggering a series of proteolytic cascade culminating into the activation of the NF-κB factors Dorsal and/or Dif (Dorsal-related immunity factor). Inappropriate activation of the Toll pathway is often associated with systemic inflammation phenotype in the absence of infection, and thus, it is important to understand the regulation of Toll signaling.
View Article and Find Full Text PDFMulticellular organisms depend on a handful of core signaling pathways that regulate a variety of cell fate choices. Often these relatively simple signals integrate to form a large and complex signaling network to achieve a distinct developmental fate in a context-specific manner. Various pathway-dependent and independent events control the assembly of signaling complexes.
View Article and Find Full Text PDFJNK signaling is a highly conserved signaling pathway that regulates a broad spectrum of cellular processes including cell proliferation, migration, and apoptosis. In Drosophila, JNK signaling is activated by binding of the tumor necrosis factor (TNF) Eiger to its receptor Wengen, and a conserved signaling cascade operates that culminates into activation of dual phosphatase Puckered thereby triggering apoptosis. The tumor necrosis factor receptor (TNFR) associated factor 6 (TRAF6) is an adaptor protein, which transduces the signal from TNFRs and Toll-like receptor/interleukin-1 receptor superfamily to induce a wide spectrum of cellular responses.
View Article and Find Full Text PDFNotch signaling is an evolutionarily conserved pathway that plays a central role in a number of cellular events during metazoan development. Due to its involvement in numerous developmental events, Notch signaling requires tight spatial and temporal regulation. Deltex is a cytoplasmic protein that physically binds to the Notch and regulates its signaling activity in a context-dependent manner.
View Article and Find Full Text PDFGene expression is regulated at multiple steps after generation of primary RNA transcripts, including mRNA processing, stability, and transport, along with co- and post-transcriptional regulation. These processes are controlled via the involvement of a multitude of RNA binding proteins (RBPs). Innumerable human diseases have been associated with altered expression of RNA binding proteins.
View Article and Find Full Text PDFNotch signaling plays a pleiotropic role in a variety of cellular processes, including cell fate determination, differentiation, proliferation and apoptosis. The increasingly complex regulatory mechanisms of Notch signaling account for the many functions of Notch during development. Using a yeast two-hybrid screen, we identified the DNA-binding protein Hat-trick (Htk) to be an interacting partner of Notch-intracellular domain (Notch-ICD); their physical interaction was further validated by co-immunoprecipitation experiments.
View Article and Find Full Text PDFThe communication among the cells plays a seminal role in metazoan development by coordinating multiple cellular processes that, in turn, helps in the maintenance of biological homeostasis. Our previous study demonstrated that Dx and Hrp48 together downregulate Notch signaling and induce cell death in Drosophila. To understand the signaling events behind the Dx and Hrp48-induced cell death in a greater detail, we performed a set of genetic experiments followed by immunocytochemical analyses.
View Article and Find Full Text PDFOwing to a multitude of functions, there is barely a tissue or a cellular process that is not being regulated by Notch signaling. To allow the Notch signal to be deployed in numerous contexts, many different mechanisms have evolved to regulate the level, duration and spatial distribution of Notch activity. To identify novel effectors of Notch signaling in Drosophila melanogaster, we analyzed the whole transcriptome of the wing and eye imaginal discs in which an activated form of Notch was overexpressed.
View Article and Find Full Text PDFTNF-JNK signaling is one of the highly conserved signaling pathways that regulate a broad spectrum of cellular processes including proliferation and apoptosis. Eiger, the sole homologue of TNF in Drosophila, initiates the TNF-JNK pathway to induce cell death. Previously, Deltex (Dx) has been identified as a Notch signaling component that regulates vesicular trafficking of Notch.
View Article and Find Full Text PDFObjectives: Oncogenic potential of Notch signaling and its cooperation with other factors to affect proliferation are widely established. Notch exhibits a cooperative effect with loss of a cell polarity gene, scribble to induce neoplastic overgrowth. Oncogenic Ras also show cooperative effect with loss of cell polarity genes such as scribble (scrib), lethal giant larvae (lgl) and discs large to induce neoplastic overgrowth and invasion.
View Article and Find Full Text PDFChromatin-remodeling proteins have a profound role in the transcriptional regulation of gene expression during development. Here, we have shown that the chromodomain-containing protein Hat-trick is predominantly expressed within the oocyte nucleus, specifically within the heterochromatinized karyosome, and that a mild expression is observed in follicle cells. Colocalization of Hat-trick with Heterochromatin Protein 1 and synaptonemal complex component C(3)G along with the diffused karyosome after downregulation shows the role of this protein in heterochromatin clustering and karyosome maintenance.
View Article and Find Full Text PDFBackground: The TP53 codon 72 Proline-Arginine polymorphism (TP53 P72R) is the most widely studied candidate among those evaluated for a putative association between impaired apoptosis and glaucoma. Considering the earlier findings about enhanced apoptotic potential by the Arg variant of TP53 P72R and the conflicting results about its association with glaucoma, we initiated a hospital-based case-control association study in a north Indian cohort to investigate the association of TP53 P72R with glaucoma.
Materials And Methods: We examined the status of TP53 P72R in 139 cases of primary open angle glaucoma (POAG) and in 111 cases of primary angle closure glaucoma (PACG) with respect to 218 controls using the polymerase chain reaction-restriction fragment length polymorphism method.
We report on a homozygous frameshift deletion in DDX59 (c.185del: p.Phe62fs*13) in a family presenting with orofaciodigital syndrome phenotype associated with a broad neurological involvement characterized by microcephaly, intellectual disability, epilepsy, and white matter signal abnormalities associated with cortical and subcortical ischemic events.
View Article and Find Full Text PDFIdentification of causal genetic defects for human diseases took a significant leap when the first generation DNA sequencing technologies enabled biologists extract sequence-based genetic information from living beings. However, these sequencing methods had unavoidable constraints of throughput, scalability, rapidity, and resolution. In this direction, next-generation sequencing (NGS) since the time of its advent has revolutionized the process of gene discovery for both monogenic and multifactorial genetic diseases.
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