Hammond, J. E. | bioRxiv Science

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↗