Biology subjects

Riddiford, N.

Publications and source records attributed to Riddiford, N..

3 recordsLinked to original sources

bioRxiv2023

Segmentation in tapeworms as a modified form of flatworm posterior regeneration involving Wnt and Hedgehog signalling

Tapeworms are parasitic flatworms that lack key features conventionally used to define the head-tail axis in free-living organisms, resulting in long standing questions regarding the true orientation of their main body axis. As adults, most tapeworms also exhibit a segmented body which has been considered an adaptation unique to the group. Anteroposterior (AP) patterning in free-living flatworms is controlled by {beta}-catenin-dependent Wnt signalling and positional control genes are expressed by their musculature in highly regionalised domains. Here we investigate the expression of Wnt and Hedgehog components during the strobilar phase of the tapeworm life cycle during which larval tissues are lost and replaced through the continuous production of new tissues. Results reveal previously unidentified centres of signalling associated with their neuromuscular system and show that segments are marked by secondary, AP axes in agreement with the polarity of the primary body axis. Neuromuscular expression and communication between Wnt and Hedgehog signalling is consistent with embryonic and regenerative growth in planarians and is a common mechanism for establishing AP-polarised boundaries in a diverse range of segmented animals. Taken together our results suggest that segmentation in tapeworms represents a modified form of posterior regeneration, a common feature among flatworms.

developmental biology↗

bioRxiv2022

Molecular Underpinnings and Environmental Drivers of Spontaneous Loss of Heterozygosity in Drosophila Intestinal Stem Cells

The genome stability of adult stem cells is of particular importance as these cells maintain long-term self-renewal capacity and can contribute extensively to adult tissues. During development and aging, genome mutation leading to loss of heterozygosity (LOH) can uncover recessive phenotypes and be propagated within tissue compartments. This phenomenon occurs in normal human tissues, and is prevalent in pathological genetic conditions and cancers. While previous studies in yeast have defined distinct DNA repair mechanisms that can promote LOH, the predominant pathways underlying LOH in complex somatic tissues of multicellular organisms arenot well understood. In addition, how environmental triggers such as pathogenic bacterial infection may impact LOH is unclear. Here, we investigate the mechanisms giving rise to LOH in adult intestinal stem cells in Drosophila. Our data indicate that infection with the enteric pathogenic bacteria, Erwinia carotovora carotovora 15 but not Pseudomonas entomophila increases LOH frequency. Using whole-genome sequencing of somatic LOH events, we demonstrate that they arise primarily via mitotic recombination. Molecular features of recombination sites and genetic evidence argue against formation via break-induced replication and instead support cross-over events arising from double Holliday junction-based repair. This study provides a mechanistic understanding of mitotic recombination in stem cells in vivo, an important mediator of LOH.

developmental biology↗

bioRxiv2020

Evolution and genomic signatures of spontaneous somatic mutation in Drosophila intestinal stem cells

Spontaneous mutations can alter tissue dynamics and lead to cancer initiation. While large-scale sequencing projects have illustrated processes that influence somatic mutation and subsequent tumour evolution, the mutational dynamics operating in the very early stages of cancer development are currently not well understood. In order to explore mutational dynamics in the early stages of cancer evolution we exploited neoplasia arising spontaneously in the Drosophila intestine. We analysed whole-genome sequencing data through the development of a dedicated bioinformatic pipeline to detect structural variants, single nucleotide variants, and indels. We found neoplasia formation to be driven largely through the inactivation of Notch by structural variants, many of which involve highly complex genomic rearrangements. Strikingly, the genome-wide mutational burden of neoplasia - at six weeks of age - was found to be similar to that of several human cancers. Finally, we identified genomic features associated with spontaneous mutation and defined the evolutionary dynamics and mutational landscape operating within intestinal neoplasia over the short lifespan of the adult fly. Our findings provide unique insight into mutational dynamics operating over a short time scale in the genetic model system, Drosophila melanogaster.

genomics↗