Biology subjects

Page, K. M.

Publications and source records attributed to Page, K. M..

7 recordsLinked to original sources

bioRxiv2025

3D epithelial cell topology tunes signalling range to promote precise patterning

Cell behaviours in multicellular organisms are coordinated via both diffusible molecules and by signals based on direct cell-cell contacts. The mode of cell communication used influences the signalling range. In many developing epithelia, contact-based Notch-Delta lateral inhibition signalling is used to pattern cell fates. While previous work revealed that cells can use protrusions to extend the range of Notch-Delta signalling to alter these patterns, this is not a general feature of epithelia. In addition, it is not known how the complex three-dimensional (3D) shapes of epithelial cells influence cell communication. In exploring this question, we show that epithelial cells at the Drosophila wing margin, which lack basal protrusions, contact different neighbours at different heights along their apico-basal axis, effectively increasing the number of neighbours each cell touches. To quantitatively assess this behaviour, we develop a novel mathematical modelling framework (Multi-layer Signalling Model) to simulate Notch-Delta signalling over data-derived 3D cell topologies. The model predicts that lateral cell surface signalling is essential to tune the spacing between SOPs. In agreement, we show that perturbing cortical stiffness and cell tortuosity in vivo modifies SOP spacing. These results emphasise the importance of 3D cell geometry and topology in fine-tuning signalling range.

developmental biology↗

bioRxiv2024

Dynamics of positional information in the vertebrate neural tube

In developing embryos, cells acquire distinct identities depending on their position in a tissue. Secreted signaling molecules, known as morphogens, act as long-range cues to provide the spatial information that controls these cell fate decisions. In several tissues, both the level and the duration of morphogen signaling appear to be important for determining cell fates. This is the case in the forming vertebrate nervous system where antiparallel morphogen gradients pattern the dorsal-ventral axis by partitioning the tissue into sharply delineated domains of molecularly distinct neural progenitors. How information in the gradients is decoded to generate precisely positioned boundaries of gene expression remains an open question. Here, we adopt tools from information theory to quantify the positional information in the neural tube and investigate how temporal changes in signaling could influence positional precision. The results reveal that the use of signaling dynamics, as well as the signaling level, substantially increases the precision possible for the estimation of position from morphogen gradients. This analysis links the dynamics of opposing morphogen gradients with precise pattern formation and provides an explanation for why time is used to impart positional information.

developmental biology↗

bioRxiv2023

Unifying evolutionary dynamics: a set theory exploration of symmetry and interaction

Within the expansive landscape of evolutionary dynamics, symmetry features embedded in well-established models significantly influence the interpretation of individual interaction patterns. Such symmetries are determined through interaction kernel functions, which serve as mathematical models for characterizing the complexity of interactions between individuals, each with distinct phenotypes. By incorporating analytical tools from logic and set theory, we aim to provide a deeper understanding of these functions, relevant to mechanisms of evolution. We prove that the kernels introduced in Champagnat et al.s unifying framework exist provided birth and death rates are symmetric with respect to non-focal traits. The kernels may nevertheless be highly challenging to construct, thereby indicating a complex underlying mathematical infrastructure within unified evolutionary dynamics. We show how interaction kernels for asymmetric frameworks arising in evolutionary graph theory can be derived by incorporating individuals graph labels into their phenotypes. These insights invite new avenues for research, providing a fresh understanding of the interactions between individuals in broader biological contexts.

evolutionary biology↗

bioRxiv2023

The interplay between splicing of exons 18a and 47 differentially affects membrane targeting and function of human CaV2.2

N-type calcium channels (CaV2.2) are predominantly localized in presynaptic terminals, and are particularly important for pain transmission in the spinal cord. Furthermore, they have multiple isoforms, conferred by alternatively-spliced or cassette exons, which are differentially expressed. Here we have examined alternatively-spliced exon47 variants that encode a long or short C-terminus in human CaV2.2. In the Ensembl database, all short exon47-containing transcripts were associated with the absence of exon 18a, therefore we also examined effect of inclusion or absence of exon18a, combinatorially with the exon47 splice variants. We found that long exon47, only in the additional presence of exon18a, results in CaV2.2 currents that have a 3.6-fold greater maximum conductance than the other three combinations. In contrast, cell surface expression of CaV2.2 in both tsA-201 cells and hippocampal neurons is increased [~]4-fold by long exon47 relative to short exon47, in either the presence or absence of exon18a. This surprising discrepancy between trafficking and function indicates that cell surface expression is enhanced by long exon47, independently of exon 18a. However, in the presence of exon47, exon18a mediates an additional permissive effect on CaV2.2 gating. We also investigated the SNP in exon47 that has been linked to schizophrenia and Parkinsons disease, which we found is only non-synonymous in the short exon47 C-terminal isoform, resulting in two minor alleles. This study highlights the importance of investigating the combinatorial effects of exon inclusion, rather than each in isolation, in order to increase our understanding of calcium channel function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=150 SRC="FIGDIR/small/557884v1_ufig1.gif" ALT="Figure 1"> View larger version (36K): org.highwire.dtl.DTLVardef@132c8fborg.highwire.dtl.DTLVardef@12910ccorg.highwire.dtl.DTLVardef@10de072org.highwire.dtl.DTLVardef@a86f7_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2022

Coupling dynamics of 2D Notch-Delta signalling

Understanding pattern formation driven by cell-cell interactions has been a significant theme in cellular biology for many years. In particular, due to their implications within many biological contexts, lateral-inhibition mechanisms present in the Notch-Delta signalling pathway led to an extensive discussion between biologists and mathematicians. Deterministic and stochastic models have been developed as a consequence of this discussion, some of which address long-range signalling by considering cell protrusions reaching non-neighbouring cells. The dynamics of such signalling systems reveal intricate properties of the coupling terms involved in these models. In this work, we examine the benefits and limitations of new and existing models of cell signalling and differentiation in a variety of contexts. Using linear and weakly nonlinear stability analyses, we find that pattern selection relies on nonlinear effects that are not covered by such analytical methods.

developmental biology↗

bioRxiv2021

Identification that ADAM17 mediates proteolytic maturation of calcium channel auxiliary α2δ subunits, and enables calcium current enhancement

The auxiliary 2{delta} subunits of voltage-gated calcium (CaV) channels are key to augmenting expression and function of CaV1 and CaV2 channels, and are also important drug targets in several therapeutic areas, including neuropathic pain. The 2{delta} proteins are translated as pre-proteins encoding both 2 and {delta}, and post-translationally proteolysed into 2 and {delta} subunits, which remain associated as a complex. In this study we have identified ADAM17 as a key protease involved in proteolytic processing of pro-2{delta}-1 and 2{delta}-3 subunits. We provide three lines of evidence: firstly, proteolytic cleavage is inhibited by chemical inhibitors of particular metalloproteases, including ADAM17. Secondly, proteolytic cleavage of both 2{delta}-1 and 2{delta}-3 is markedly reduced in cell lines by knockout of ADAM17 but not ADAM10. Thirdly, proteolytic cleavage is reduced by the N-terminal active domain of TIMP-3 (N-TIMP-3), which selectively inhibits ADAM17. We have found previously that proteolytic cleavage into mature 2{delta} is essential for the enhancement of CaV function, and in agreement, knockout of ADAM17 inhibited the ability of 2{delta}-1 to enhance both CaV2.2 and CaV1.2 calcium currents. Thus, our study identifies ADAM17 as a key protease required for proteolytic maturation of 2{delta}-1 and 2{delta}-3, and thus a potential drug target in neuropathic pain.

neuroscience↗

bioRxiv2021

"Neighborhood watch" model: embryonic epiblast cells assess positional information in relation to their neighbors

In many developing and regenerating systems, tissue pattern is established through gradients of informative morphogens, but we know little about how cells interpret these. Using experimental manipulation of early chick embryos including misexpression of an inducer (VG1 or ACTIVIN) and an inhibitor (BMP4), we test two alternative models for their ability to explain how the site of primitive streak formation is positioned relative to the rest of the embryo. In one model, cells read morphogen concentrations cell-autonomously. In the other, cells sense changes in morphogen status relative to their neighbourhood. We find that only the latter model can account for the experimental results, including some counter-intuitive predictions. This mechanism (which we name "neighbourhood watch" model) illuminates the classic "French Flag Problem" and how positional information is interpreted by a sheet of cells in a large developing system. Summary statementIn a large developing system, the chick embryo before gastrulation, cells interpret gradients of positional signals relative to their neighbours to position the primitive streak, establishing bilateral symmetry.

developmental biology↗