Biology subjects

Thor, S.

Publications and source records attributed to Thor, S..

6 recordsLinked to original sources

bioRxiv2026

A coordinated morphogenetic program drives rapid body plan transformation in a sponge

Across the animal kingdom, metamorphosis transforms a free-swimming larva into a morphologically distinct juvenile, yet how conserved cellular processes are spatiotemporally coordinated to execute this rapid body plan switch remains poorly understood. Using the marine sponge Amphimedon queenslandica -- a member of one of the earliest-diverging animal phyletic lineages -- we characterise the cellular and morphogenetic events of the first six hours of metamorphosis. We show that metamorphosis proceeds through a tightly ordered sequence of events orchestrated by a stereotypic wave of epithelial infoldings that propagates from the basal to the apical pole within the first hour post-settlement. This wave acts as a morphogenetic pacemaker, spatially and temporally inducing subsequent cellular transitions, which include coordinated mucus secretion, cilia resorption, epithelial-mesenchymal transition (EMT), mesenchymal-epithelial transition (MET), transdifferentiation and targeted programmed cell death. Lineage tracing further reveals the stepwise transformation of larval cells at metamorphosis, with labelled epithelial flask cells transdifferentiating into internal archaeocyte stem cells via a transitory amoeboid cell state associated with EMT. These findings demonstrate that rapid metamorphosis comprises a spatially pre-patterned, stepwise program, and provide a cellular framework for understanding body plan transformations with broad implications for the evolution of metazoan metamorphosis.

developmental biology↗

bioRxiv2026

Vgll2 and Tead1 Govern Generation of Mouse and Human Hypothalamic Hypocretin (Orexin) Neurons

The hypothalamic hypocretin (Hcrt; aka orexin) neuropeptide neurons are crucial for wakefulness and their malfunction results in narcolepsy; a devastating disorder without current cures. Transplantation of mouse Hcrt cells into mouse narcolepsy models is pointing to cell therapy as a potential treatment for narcolepsy. However, progress in this area requires decoding the developmental pathways generating human HCRT neurons and a deeper understanding of their diversity and physiology. Here, we identify the hypothalamic progenitor domain generating mouse Hcrt neurons and propose a conserved mouse/human genetic cascade driving Hcrt specification. This cascade involves the Vgll2 and Tead1 transcription factor partners, which we find are crucial for mouse Hcrt neuron generation. Conversely, co-misexpression of VGLL2 and TEAD1 in human stem cell derived hypothalamic organoids can induce HCRT neuron differentiation. These findings provide an important element for the development of human induced HCRT neurons for physiological studies and for cell therapy in narcolepsy.

neuroscience↗

bioRxiv2023

Polycomb Repressive Complex 2 is critical for mouse cortical glutamatergic neuron development

The Polycomb Repressive Complex 2 (PRC2) regulates corticogenesis, yet the consequences of mutations to this epigenetic modifier in the mature brain are poorly defined. Importantly, PRC2 core genes are haploinsufficient and causative for several human neurodevelopmental disorders. To address the role of PRC2 in mature cortical structure and function, we conditionally mutated the PRC2 gene Eed in the developing mouse telencephalon. Adult homozygotes displayed smaller forebrain structures. Single-nucleus transcriptomics revealed glutamatergic neurons were particularly affected, exhibiting dysregulation of cortical layer-specific profiles, accompanied by aberrations in neuronal morphology and connectivity. Incredibly, homozygous mice performed well on challenging cognitive tasks. In contrast, heterozygous mice did not exhibit anatomical or behavioral phenotypes but displayed dysregulation of neuronal genes and altered neuronal morphology that was strikingly different from homozygous phenotypes. Collectively, we demonstrate how alterations to PRC2 function shape the mature brain and reveal a dose-specific role for PRC2 in determining glutamatergic neuron identity.

developmental biology↗

bioRxiv2022

Cytocipher detects significantly different populations of cells in single cell RNA-seq data

Identification of cell types using single cell RNA-seq (scRNA-seq) is revolutionising the study of multicellular organisms. However, typical scRNA-seq analysis often involves post hoc manual curation to ensure clusters are transcriptionally distinct, which is time-consuming, error-prone, and irreproducible. To overcome these obstacles, we developed Cytocipher, a bioinformatics method and scverse compatible software package that statistically determines significant clusters. Application of Cytocipher to normal tissue, development, disease, and large-scale atlas data reveals the broad applicability and power of Cytocipher to generate biological insights in numerous contexts. This included the identification of cell types not previously described in the datasets analyzed, such as CD8+ T cell subtypes in human peripheral blood mononuclear cells; cell lineage intermediate states during mouse pancreas development; and subpopulations of luminal epithelial cells over-represented in prostate cancer. Cytocipher also scales to large datasets with high test performance, as shown by application to the Tabula Sapiens Atlas representing >480,000 cells. Cytocipher is a novel and generalisable method that statistically determines transcriptionally distinct and programmatically reproducible clusters from single cell data. Cytocipher is available at https://github.com/BradBalderson/Cytocipher.

bioinformatics↗

bioRxiv2021

Deep Learning Decodes Multi-layered Roles of Polycomb Repressor Complex 2 During Mouse CNS Development

A prominent aspect of most, if not all, central nervous systems (CNSs) is that anterior regions (brain) are larger than posterior ones (spinal cord). Studies in Drosophila and mouse have revealed that the Polycomb Repressor Complex 2 (PRC2), a protein complex responsible for applying key repressive histone modifications, acts by several mechanisms to promote anterior CNS expansion. However, it is unclear what the full spectrum of PRC2 action is during embryonic CNS development and how PRC2 integrates with the epigenetic landscape. We removed PRC2 function from the developing mouse CNS, by mutating the key gene Eed, and generated spatio-temporal transcriptomic data. To decode the role of PRC2, we developed a method that incorporates standard statistical analyses with probabilistic deep learning to integrate the transcriptomic response to PRC2 inactivation with epigenetic information from ENCODE. This multi-variate analysis corroborates the central involvement of PRC2 in anterior CNS expansion, and reveals layered regulation via PRC2. These findings uncover a differential logic for the role of PRC2 upon functionally distinct gene categories that drive CNS anterior expansion. To support the analysis of emerging multi-modal datasets, we provide a novel bioinformatics package that integrates transcriptomic and epigenetic datasets to identify regulatory underpinnings of heterogeneous biological processes.

bioinformatics↗

bioRxiv2019

Drosophila Neuroblast Selection Gated by Notch, Snail, SoxB and EMT Gene Interplay

In the developing Drosophila central nervous system neural progenitor (neuroblast; NB) selection is gated by lateral inhibition, controlled by Notch signalling and proneural genes. However, proneural mutants only display partial NB reduction, indicating the existence of additional genes with proneural activity. In addition, recent studies reveal involvement of key epithelial-mesenchymal transition (EMT) genes in NB selection, but the regulatory interplay between Notch signalling and the EMT machinery is unclear. We find that the SoxB gene SoxNeuro and the Snail gene worniou are integrated with the Notch pathway, and constitute the missing proneural genes. Notch signalling, the proneural, SoxNeuro, and worniou genes regulate key EMT genes to orchestrate the NB specification process. Hence, we uncover an expanded lateral inhibition network for NB specification, and demonstrate its link to key players in the EMT machinery. Because of the evolutionary conservation of the genes involved, the Notch-SoxB-Snail-EMT network may control neural progenitor selection in many other systems.

developmental biology↗