Biology subjects

Hausmann, G.

Publications and source records attributed to Hausmann, G..

6 recordsLinked to original sources

bioRxiv2024

Activation of the innate immune system accelerates growth in cooperation with oncogenic Ras

Innate immunity in Drosophila acts as an organismal surveillance system that measures external stimuli or cellular fitness and triggers context-specific responses to fight infections and maintain tissue homeostasis. However, uncontrolled activation of innate immune pathways can be detrimental to the system. In mammals, innate immune signaling is often overactivated in malignant cells and contributes to tumor progression. Drosophila tumor models have been instrumental in the discovery of interactions between pathways that promote tumorigenesis, but little is known about whether and how the Toll innate immune pathway interacts with oncogenes. Here we use a Drosophila epithelial in vivo model to investigate the interplay between Toll signaling and oncogenic Ras. In absence of oncogenic Ras, Toll signaling suppresses differentiation and induces apoptosis. In contrast, in the context of RasV12, cells are protected from cell death and Dorsal promotes cell survival and proliferation to drive hyperplasia. Taken together, we show that the tissue-protective functions of innate immune activity can be hijacked by pre-malignant cells to induce oncogenic transformation.

cancer biology↗

bioRxiv2022

Terminal differentiation of enterocytes is governed by distinct members of Tgfβ superfamily

The protective and absorptive functions of the intestinal epithelium rely on differentiated enterocytes in the villi. The differentiation of enterocytes is orchestrated by sub-epithelial mesenchymal cells producing distinct ligands along the villus axis, in particular Bmps and Tgf{beta}. Here we show that individual Bmp ligands and Tgf{beta} drive distinct enterocytic programs specific to villus zonation. Bmp4 is expressed mainly from the center to the upper part of the villus, and it activates preferentially genes connected to lipid uptake and metabolism. In contrast, Bmp2 is produced by villus-tip mesenchymal cells, and it influences the adhesive properties of villus-tip epithelial cells and the expression of immunomodulators. Hence, Bmp2 promotes the terminal enterocytic differentiation at the villus-tip. Additionally, Tgf{beta} induces epithelial gene expression programs similar to that triggered by Bmp2. The inhibition of Bmp receptor type I in vivo and using intestinal organoids lacking Smad4 revealed that Bmp2-driven villus-tip program is activated by a canonical Smad-dependent mechanism. Finally, we established an organoid cultivation system that enriches for villus-tip enterocytes and thereby better mimics the cellular composition of the intestinal epithelium. Altogether our data suggest that not only Bmp gradient, but also the activity of individual Bmp drives specific enterocytic programs.

cell biology↗

bioRxiv2021

Manipulating the murine Lgr5 locus using a rapid, efficient and flexible CRISPR/Cas9 pipeline

The maintenance of adult epithelial tissues, such as the lining of the intestine, depends on their periodical renewal. This is achieved through small populations of adult stem cells. Lgr5 serves as a marker for these cells. Here we report a novel non-variegated Lgr5 mouse model, which was generated via the CRISPR/Cas9 system. We show that this Lgr5-2A-CreERT2-2A-mOrange2 mouse line can be used for lineage tracing, as well as for directing gene expression to Lgr5+ cells. The introduction of the transgene affects neither the expression, nor the function of endogenous Lgr5. Therefore, this new tool will serve to mark and manipulate intestinal stem cells to gain new biological insights.

developmental biology↗

bioRxiv2020

Discrete regulation of b-catenin-mediated transcription governs identity of intestinal epithelial stem cells

The homeostasis of the gut epithelium relies upon continuous renewal and proliferation of crypt-resident intestinal epithelial stem cells (IESCs). Wnt/{beta}-catenin signaling is required for IESC maintenance, however, it remains unclear how this pathway selectively governs the identity and proliferative decisions of IESCs. Here, we demonstrate that C-terminally-recruited transcriptional co-factors of {beta}-catenin act as all-or-nothing regulators of Wnt-target gene expression. Blocking their interactions with {beta}-catenin rapidly induces loss of IESCs and intestinal homeostasis. Conversely, N-terminally recruited co-factors fine-tune {beta}-catenins transcriptional output to ensure proper self-renewal and proliferative behaviour of IESCs. Impairment of N-terminal interactions triggers transient hyperproliferation of IESCs, eventually resulting in exhaustion of the self-renewing stem cell pool. IESC mis-differentiation, accompanied by intrinsic and extrinsic stress signalling results in a process resembling aberrant "villisation" of intestinal crypts. Our data suggest that IESC-specific Wnt/{beta}-catenin output requires discrete regulation of transcription by transcriptional co-factors.

cell biology↗

bioRxiv2019

Cryo-EM structure of the Hedgehog release protein Dispatched

The Hedgehog signaling pathway controls embryonic development and adult tissue homeostasis in multicellular organisms. In Drosophila melanogaster, the pathway is primed by secretion of a dually lipid-modified morphogen, Hedgehog (Hh), a process dependent on a membrane-integral protein Dispatched. Although Dispatched is a critical component of the pathway, the structural basis of its activity has so far not been described. Here, we describe a cryo-EM structure of the Drosophila melanogaster Dispatched at 3.2 [A] resolution. The ectodomains of Dispatched adopt an open conformation suggestive of a receptor-chaperone role. A 3D reconstruction of Dispatched bound to Hh confirms the ability of Dispatched to bind Hh but using a unique mode distinct from those previously observed in structures of Hh complexes. The structure may represent the state of the complex that precedes shedding of Hh from the surface of the morphogen-releasing cell.

biochemistry↗

bioRxiv2018

Mutations in Bcl9 and Pygo genes cause congenital heart defects by tissue-specific perturbation of Wnt/β-catenin signaling

Genetic alterations in human BCL9 genes have repeatedly been found in congenital heart disease (CHD) with as-of-yet unclear causality. BCL9 proteins and their Pygopus (Pygo) co-factors can participate in canonical Wnt signaling via binding to {beta}-catenin. Nonetheless, their contributions to vertebrate heart development remain uncharted. Here, combining zebrafish and mouse genetics, we document tissue-specific functions in canonical Wnt signaling for BCL9 and Pygo proteins during heart development. In a CRISPR-Cas9-based genotype-phenotype association screen, we uncovered that zebrafish mutants for bcl9 and pygo genes largely retain {beta}-catenin activity, yet develop cardiac malformations. In mouse, both systemic and lineage-specific loss of the Pygo-BCL9-{beta}-catenin complex caused heart defects with outflow tract malformations, aberrant cardiac septation and valve formation, and compact myocardium hypoplasia. Mechanistically, these phenotypes coincide with transcriptional deregulation during heart patterning, and Pygo2 associates with {beta}-catenin at cis-regulatory regions of cardiac genes. Taken together, our results establish BCL9 and Pygo as tissue-specific {beta}-catenin co-factors during vertebrate heart development. Our results further implicate alterations in BCL9 and BCL9L in human CHDs as possibly causative.

genetics↗