ORCID Profile
0000-0001-5726-7791
Current Organisations
Osmania University Nizam College
,
University of Oxford
,
Columbia University
,
Jesus College
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Publisher: Springer Science and Business Media LLC
Date: 24-11-2017
DOI: 10.1038/S41467-017-02002-4
Abstract: Mutations in PIK3CA are very frequent in cancer and lead to sustained PI3K pathway activation. The impact of acute expression of mutant PIK3CA during early stages of malignancy is unknown. Using a mouse model to activate the Pik3ca H1047R hotspot mutation in the heterozygous state from its endogenous locus, we here report that mutant Pik3ca induces centrosome lification in cultured cells (through a pathway involving AKT, ROCK and CDK2/Cyclin E-nucleophosmin) and in mouse tissues, and increased in vitro cellular tolerance to spontaneous genome doubling. We also present evidence that the majority of PIK3CA H1047R mutations in the TCGA breast cancer cohort precede genome doubling. These previously unappreciated roles of PIK3CA mutation show that PI3K signalling can contribute to the generation of irreversible genomic changes in cancer. While this can limit the impact of PI3K-targeted therapies, these findings also open the opportunity for therapeutic approaches aimed at limiting tumour heterogeneity and evolution.
Publisher: Wiley
Date: 14-07-2015
DOI: 10.1002/DVDY.24300
Abstract: Amniote gastrulation is often described with respect to human, mouse and chick development by the presence of the primitive streak, a posterior-to-anterior midline morphological cell ingression feature that has come to define Amniote gastrulation. How this midline, ingression-based strategy of gastrulation evolved from the ancestral blastopore, a circumferential involution event in Anamniotes, is unknown. However, within the Amniote clade there exists a more erse range of gastrulation strategies than just the primitive streak. Investigating gastrulation in a wider range of Amniotes provides a way to understand evolutionary transition from blastopore to the primitive streak. We analysed early to late gastrulation stages of Chamaeleo calyptratus, showing their unique morphology through confocal imaging of F-actin and laminin-stained embryos to visualise cell morphology and assess basal lamina integrity. We analysed the expression pattern of core mesodermal markers Brachyury and Fgf8 and complimented this analysis with that of the turtle, Trachemys scripta. Our analysis suggests that reptile gastrulation is bi-modal primary internalization occurs anteriorly by means of an incomplete blastopore-like opening, while posteriorly the cells undergo ingression in the Brachyury-expressing blastoporal plate. This strategy stands mid-way between Anamniotes and Avians/Mammals, suggesting that blastoporal plate is a precursor of the avian primitive streak. Developmental Dynamics 244:1144-1157, 2015. © 2015 Wiley Periodicals, Inc.
Publisher: eLife Sciences Publications, Ltd
Date: 11-10-2016
DOI: 10.7554/ELIFE.17113
Abstract: The mammalian heartbeat is thought to begin just prior to the linear heart tube stage of development. How the initial contractions are established and the downstream consequences of the earliest contractile function on cardiac differentiation and morphogenesis have not been described. Using high-resolution live imaging of mouse embryos, we observed randomly distributed spontaneous asynchronous Ca2+-oscillations (SACOs) in the forming cardiac crescent (stage E7.75) prior to overt beating. Nascent contraction initiated at around E8.0 and was associated with sarcomeric assembly and rapid Ca2+ transients, underpinned by sequential expression of the Na+-Ca2+ exchanger (NCX1) and L-type Ca2+ channel (LTCC). Pharmacological inhibition of NCX1 and LTCC revealed rapid development of Ca2+ handling in the early heart and an essential early role for NCX1 in establishing SACOs through to the initiation of beating. NCX1 blockade impacted on CaMKII signalling to down-regulate cardiac gene expression, leading to impaired differentiation and failed crescent maturation.
Publisher: Cold Spring Harbor Laboratory
Date: 21-11-2020
DOI: 10.1101/2020.11.20.391896
Abstract: Transcriptional and epigenetic profiling of single-cells has advanced our knowledge of the molecular bases of gastrulation and early organogenesis. However, current approaches rely on dissociating cells from tissues, thereby losing the crucial spatial context that is necessary for understanding cell and tissue interactions during development. Here, we apply an image-based single-cell transcriptomics method, seqFISH, to simultaneously and precisely detect mRNA molecules for 387 selected target genes in 8-12 somite stage mouse embryo tissue sections. By integrating spatial context and highly multiplexed transcriptional measurements with two single-cell transcriptome atlases we accurately characterize cell types across the embryo and demonstrate how spatially-resolved expression of genes not profiled by seqFISH can be imputed. We use this high-resolution spatial map to characterize fundamental steps in the patterning of the midbrain-hindbrain boundary and the developing gut tube. Our spatial atlas uncovers axes of resolution that are not apparent from single-cell RNA sequencing data – for ex le, in the gut tube we observe early dorsal-ventral separation of esophageal and tracheal progenitor populations. In sum, by computationally integrating high-resolution spatially-resolved gene expression maps with single-cell genomics data, we provide a powerful new approach for studying how and when cell fate decisions are made during early mammalian development.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Shankar Srinivas.