Biology subjects

Theelke, J.

Publications and source records attributed to Theelke, J..

4 recordsLinked to original sources

bioRxiv2023

Postnatal FGF-signalling establishes gradients of cell-identities along the proximal-distal axis of the lung airways

Secretory cells are major structural and functional constituents of the lung airways. Their spatial organization and specification mechanisms are partially understood. Here, we labelled major secretory airway cell types and analysed them at single-cell resolution. We found opposing, partially overlapping gene-expression gradients along the proximal-distal airway axis superimposed on a general gene program encoding detoxification. One graded program is elevated proximally and relates to innate immunity, whereas the other is enriched distally, encoding lipid metabolism and antigen presentation. Intermediately positioned cells express low levels of both graded programs and show increased clonogenic potency in vitro, relating cell-plasticity to location in each branch. Single-cell RNA-sequencing following lineage-tracing revealed the sequential and postnatal establishment of the gradients in common epithelial progenitors. Fgfr2b is distally enriched and its postnatal inactivation reduces distal gene expression and expands proximal genes into distally located cells. This suggests a central role of FGFR-signaling in tissue-scale airway patterning.

cell biology↗

bioRxiv2022

Developmental origins of cell heterogeneity in the human lung

The lung contains numerous specialized cell-types with distinct roles in tissue function and integrity. To clarify the origins and mechanisms generating cell heterogeneity, we created a first comprehensive topographic atlas of early human lung development. We report 83 cell states, several spatially-resolved developmental trajectories and predict cell interactions within defined tissue niches. We integrated scRNA-Seq and spatial transcriptomics into a web-based, open platform for interactive exploration. To illustrate the utility of our approach we show distinct states of secretory and neuroendocrine cells, largely overlapping with the programs activated either during lung fibrosis or small cell lung cancer progression. We define the origin of uncharacterized airway fibroblasts associated with airway smooth muscle in bronchovascular bundles, and describe a trajectory of Schwann cell progenitors to intrinsic parasympathetic neurons controlling bronchoconstriction. Our atlas provides a rich resource for further research and a reference for defining deviations from homeostatic and repair mechanisms leading to pulmonary diseases.

developmental biology↗

bioRxiv2020

Tissue interactions govern pattern formation in the posterior lateral line of medaka

Vertebrate organs are arranged in a stereotypic, species-specific position along the animal body plan. Substantial morphological variation exists between related species, especially so in the vastly diversified teleost clade. It is still unclear how tissues, organs and systems can accommodate such diverse scaffolds. Here, we use the sequential formation of neuromasts in the posterior lateral line (pLL) system of medaka fish to address tissue-interactions defining a pattern. We show that the pLL pattern is established independently of its neuronal wiring, and demonstrate that the neuromast precursors that constitute the pLL behave as autonomous units during pattern construction. We uncover the necessity of epithelial integrity for correct pLL patterning by disrupting keratin 15 (krt15) and creating epithelial lesions that lead to novel neuromast positioning. By using krt15/wt chimeras, we determined that the new pLL pattern depends exclusively on the mutant epithelium, which instructs wt neuromast to locate ectopically. Inducing epithelial lesions by 2-photon laser ablation during pLL morphogenesis phenocopies krt15 genetic mutants and reveals that epithelial integrity defines the final position of the embryonic pLL neuromasts. Our results show that a fine-balance between primordium intrinsic properties and instructive interactions with the surrounding tissues is necessary to achieve proper organ morphogenesis and patterning. We speculate that this logic likely facilitates the accommodation of sensory modules to changing and diverse body plans.

developmental biology↗

bioRxiv2018

An ATF4-mediated transcriptional adaptation of electron transport chain disturbance primes progenitor cells for proliferation in vivo

The mitochondrial electron transport chain (ETC) enables many important metabolic reactions, like ATP generation and redox balance. While the vital importance of mitochondrial function is obvious, the cellular response to defects in mitochondria and in particular the modulation of signalling pathway outputs is not understood. Using the Drosophila eye as model, we show that the combination of Notch signalling and a mild attenuation of the ETC via knock-down of COX7a causes massive cellular over-proliferation. The tumour like growth is caused by a transcriptional response through the eIF2-kinase PERK and ATF4, a stress-induced transcription factor, which activates the expression of many metabolic enzymes, nutrient transporters and mitochondrial chaperones. We find this stress adaptation to be beneficial for progenitor cell fitness upon ETC attenuation. Activation of the ATF4 mediated stress response renders cells sensitive to proliferation induced by the growth-promoting Notch or Ras signalling pathways, leading to severe tissue over-growth. In sum, our results suggest ETC function is monitored by the PERK-ATF4 pathway, a cellular adaptation hijacked by growth-promoting signalling pathways in situations of oncogenic pathway activity.

developmental biology↗