Biology subjects

Hammond, J. E.

Publications and source records attributed to Hammond, J. E..

3 recordsLinked to original sources

bioRxiv2026

Evolving initial conditions: an alternative developmental route to morphological diversity

Phenotypic diversity is often thought to arise from the evolutionary modification of developmental processes. However, developmental processes are tightly coupled in space and time, with each process beginning from conditions set by the one before it. While we know from dynamical systems theory that initial conditions can significantly affect a systems out-come, their importance as a source of phenotypic evolvability has been largely overlooked. Here we show for the first time, that phenotypic evolution can proceed through changes in developmental initial conditions while the underlying developmental process remains conserved. Somitogenesis is the process by which vertebral precursors, known as somites, are periodically patterned in the pre-somitic mesoderm (PSM). Somitic count (total number of somites) is thought to diversify through the evolution of components of somitogenesis such as the tempo of the segmentation clock or the mechanisms driving axial morphogenesis. Using two closely related species of Lake Malawi cichlid fishes that differ in vertebral counts, we show that somite count evolution has happened without changes to somitogenesis itself, but instead, by altering the size of the PSM at the onset of this process. This work will expand what we consider developmental drivers of phenotypic evolution and highlight the importance of comparative studies to understand the diversification of phenotypes.

developmental biology↗

bioRxiv2024

Modularity of the segmentation clock and morphogenesis

Vertebrates have evolved great diversity in the number of segments dividing the trunk body, however the developmental origin of the evolvability of this trait is poorly understood. The number of segments is thought to be determined in embryogenesis as a product of morphogenesis of the pre-somitic mesoderm (PSM) and the periodicity of a molecular oscillator active within the PSM known as the segmentation clock. Here we explore whether the clock and PSM morphogenesis exhibit developmental modularity, as independent evolution of these two processes may explain the high evolvability of segment number. Using a computational model of the clock and PSM parameterised for zebrafish, we find that the clock is broadly robust to variation in morphogenetic processes such as cell ingression, motility, compaction, and cell division. We show that this robustness is in part determined by the length of the PSM and the strength of phase coupling in the clock. As previous studies report no changes to morphogenesis upon perturbing the clock, we suggest that the clock and morphogenesis of the PSM exhibit developmental modularity.

developmental biology↗

bioRxiv2021

The orphan drug dichloroacetate reduces amyloid beta-peptide production whilst promoting non-amyloidogenic proteolysis of the amyloid precursor protein

The amyloid cascade hypothesis proposes that excessive accumulation of amyloid beta-peptides is the initiating event in Alzheimers disease. These neurotoxic peptides are generated from the amyloid precursor protein via sequential cleavage by {beta}- and {gamma}-secretases in the amyloidogenic proteolytic pathway. Alternatively, the amyloid precursor protein can be processed via the non-amyloidogenic pathway which, through the action of the -secretase a disintegrin and metalloproteinase (ADAM) 10, both precludes amyloid beta-peptide formation and has the additional benefit of generating a neuroprotective soluble amyloid precursor protein fragment, sAPP. In the current study, we investigated whether the orphan drug, dichloroacetate, could alter amyloid precursor protein proteolysis. In SH-SY5Y neuroblastoma cells, dichloroacetate enhanced sAPP generation whilst inhibiting {beta}-secretase processing of endogenous amyloid precursor protein and the subsequent generation of amyloid beta-peptides. Over-expression of the amyloid precursor protein partly ablated the effect of dichloroacetate on amyloidogenic and non-amyloidogenic processing whilst over-expression of the {beta}-secretase only ablated the effect on amyloidogenic processing. Similar enhancement of ADAM-mediated amyloid precursor protein processing by dichloroacetate was observed in unrelated cell lines and the effect was not exclusive to the amyloid precursor protein as an ADAM substrate, as indicated by dichloroacetate-enhanced proteolysis of the Notch ligand, Jagged1. Despite altering proteolysis of the amyloid precursor protein, dichloroacetate did not significantly affect the expression of -, {beta}- or {gamma}-secretases. In conclusion, dichloroacetate can inhibit amyloidogenic and promote non-amyloidogenic proteolysis of the amyloid precursor protein. As the drug is already used for the treatment of lactic acidosis and is known to cross the blood-brain-barrier, it might represent a cheap and effective therapy for slowing the progression of Alzheimers disease.

cell biology↗