Biology subjects

Haas, A.

Publications and source records attributed to Haas, A..

9 recordsLinked to original sources

bioRxiv2026

The molecular basis of hard cornification in the keratinized jaw sheaths and keratodonts of anuran tadpoles

Hard cornification is the developmental process that produces the hardened epidermal structures that characterize tetrapod diversity, including scales, feathers, hair, and claws. This process relies on keratin proteins and additional reinforcing proteins that assemble, cross-link, and strengthen tissues to become mechanically resilient. Although the molecular composition of hard cornified tissues is known to vary among tetrapods, the program is least understood in amphibians. Within frogs, hard cornification occurs in the mouthparts of most tadpoles and in the nuptial pads, hindfoot claws, and foot tubercles of some adults. We characterized transcriptomic profiles of Bombina orientalis tadpoles at three developmental stages before, during, and after mouthpart cornification. We identified 25 keratin genes orthologous to amniote hard keratins in the B. bombina genome, 18 of which are upregulated in cornifying larval mouthparts. Furthermore, two of these hard keratin paralogs and an amphibian epidermal differentiation gene exhibit distinct spatial expression patterns within the jaw sheaths and keratodonts evidenced by in situ hybridization, suggesting they have discrete functional roles. The newly discovered diversity of the hard keratin repertoire in Bombina , and the concurrent expression of many of these paralogs in tadpole mouthparts, suggests that anuran hard cornification is much more complex than adult cornified traits thus far characterized in Xenopus frogs. Our results also challenge the notion that the diversification of keratins in Amphibia is primarily associated with the transition to more terrestrial habits, and may instead be shaped, in part, by the novel feeding apparatus of aquatic tadpoles.

evolutionary biology↗

bioRxiv2026

Cancer drives atherosclerotic plaque vulnerability by inducing pathological angiogenesis

Cardiovascular disease (CVD) is the leading cause of death for many cancer survivors, a phenomenon traditionally attributed to shared risk factors and cardiotoxic chemotherapies. Here, we hypothesized that cancer may also directly promote atherosclerosis. Propensity-matched analyses confirmed significantly elevated cardiovascular event rates amongst cancer patients, independent of comorbidities such as smoking. Atheroprone mice implanted with colorectal tumors demonstrated accelerated features of plaque vulnerability, driven by pathological angiogenesis and intraplaque hemorrhage. Mechanistically, tumor-secreted TNF- induced the pro-angiogenic factor LRG1 across multiple murine models and human plaques. Therapeutic interventions targeting these pathways, including with FDA-approved cytokine inhibitors or tumor resection, prevented plaque destabilization in mice and reduced coronary revascularization rates in patients. Together, these findings suggest that cancer may causally promote CVD and unveil novel translational strategies for cancer survivors.

pathology↗

bioRxiv2025

Wnt10b signaling regulates replication stress-induced chromosomal instability in human cancer

Wnt signaling pathways are involved in various developmental and tissue maintenance functions while deregulated Wnt signaling is closely linked to human cancer. Recent work revealed that loss of Wnt signaling impairs mitosis and causes abnormal microtubule growth at the mitotic spindle resulting in chromosome missegregation and aneuploidy, both of which are hallmarks of cancer cells exhibiting chromosomal instability (CIN). Here, we demonstrate that Wnt signaling specifically activated by Wnt10b is relevant in colorectal cancer cells to prevent abnormal microtubule dynamics and chromosome missegregation. Although mitosis is affected, Wnt10b signaling is required during the S phase of the cell cycle. In fact, Wnt10b signaling acts upon DNA replication stress in S phase, a condition typically associated with CIN in cancer, to prevent increased microtubule dynamics from S phase until mitosis, where they otherwise manifest in chromosome missegregation. Interestingly, replication stress-induced chromosomal breaks are also efficiently suppressed by Wnt10b. Thus, our results show that Wnt10b signaling regulates replication stress-induced chromosome missegregation and breakage, and hence, is a determinant for broad genome instability in cancer cells. Summary blurbWe describe a novel role of Wnt10b signaling acting in response to DNA replication stress to suppress chromosomal breaks and mitotic errors in human cancer cells.

cell biology↗

bioRxiv2024

CRASH2p: Closed-loop Two Photon Imaging in Freely Moving Animals

Direct measurement of neural activity in freely moving animals is essential for understanding how the brain controls and represents behaviors. Genetically encoded calcium indicators report neural activity as changes in fluorescence intensity, but brain motion confounds quantitative measurement of fluorescence. Translation, rotation, and deformation of the brain and the movements of intervening scattering or auto-fluorescent tissue all alter the amount of fluorescent light captured by a microscope. Compared to single-photon approaches, two photon microscopy is less sensitive to scattering and off-target fluorescence, but more sensitive to motion, and two photon imaging has always required anchoring the microscope to the brain. We developed a closed-loop resonant axial-scanning high-speed two photon (CRASH2p) microscope for real-time 3D motion correction in unrestrained animals, without implantation of reference markers. We complemented CRASH2p with a novel scanning strategy and a multi-stage registration pipeline. We performed volumetric ratiometrically corrected functional imaging in the CNS of freely moving Drosophila larvae and discovered previously unknown neural correlates of behavior.

neuroscience↗

bioRxiv2023

TRPM2-CaMKII signaling drives excessive GABAergic synaptic inhibition following ischemia

Following an ischemic insult to the brain, there is an acute loss of GABAergic inhibitory synapses and an increase in excitatory/ inhibitory (E/I) imbalance that drives neuronal hyperexcitability. It is unknown whether this E/I imbalance persists at delayed timepoints and contributes to chronic impairments in memory and long-term potentiation (LTP) in the hippocampus following ischemic brain injury. Here, we reveal a shift to reduced E/I ratio in hippocampal CA1 neurons via a persistent increase in postsynaptic GABAA receptor mediated inhibitory responses and clustering days after a global ischemic insult. This enhancement of postsynaptic inhibitory function and clustering required activation of the Ca2+-permeable TRPM2 ion channel and the Ca2+-dependent kinase, CaMKII. Thus, we propose a mechanism in which acute downregulation of GABAA receptors is followed by a strengthening of inhibitory synapses at delayed periods after ischemia. Targeting this mechanism has therapeutic potential to recover hippocampal plasticity and cognitive function post-ischemia. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=123 SRC="FIGDIR/small/556550v1_ufig1.gif" ALT="Figure 1"> View larger version (26K): org.highwire.dtl.DTLVardef@16ef5f2org.highwire.dtl.DTLVardef@1d51f19org.highwire.dtl.DTLVardef@ecc726org.highwire.dtl.DTLVardef@106cdd0_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2023

A signalling rheostat controls chromosome segregation fidelity during early lineage specification and neurogenesis by modulating DNA replication stress

The development and homeostasis of organisms rely on the correct replication, maintenance and segregation of their genetic blueprints. How these intracellular processes are monitored across generations of different human cellular lineages, and why the spatio-temporal distribution of mosaicism varies during development remain unknown. Here, we identify several lineage specification signals that regulate chromosome segregation fidelity in both human and mouse pluripotent stem cells. Through epistatic analyses, we find that that WNT, BMP and FGF form a signalling "rheostat" upstream of ATM that monitors replication fork velocity, origin firing and DNA damage during S-phase in pluripotency, which in turn controls spindle polymerisation dynamics and faithful chromosome segregation in the following mitosis. Cell signalling control of chromosome segregation fidelity declines together with ATM activity after pluripotency exit and specification into the three human germ layers, or further differentiation into meso- and endoderm lineages, but re-emerges during neuronal lineage specification. In particular, we reveal that a tug-of-war between FGF and WNT signalling in neural progenitor cells results in DNA damage and chromosome missegregation during cortical neurogenesis, which could provide a rationale for the high levels of mosaicism in the human brain. Our results highlight a moonlighting role of morphogens, patterning signals and growth factors in genome maintenance during pluripotency and lineage specification, which could have important implications for our understanding on how mutations and aneuploidy arise during human development and disease. One sentence summaryDevelopmental signals link genome maintenance to cell fate

cell biology↗

bioRxiv2023

PKCδ regulates chromatin remodeling and DNA repair through SIRT6

Protein kinase C delta (PKC{delta}) is a ubiquitous kinase whose function is defined in part by localization to specific cellular compartments. Nuclear PKC{delta} is both necessary and sufficient for IR-induced apoptosis, while inhibition of PKC{delta} activity provides radioprotection in vivo. How nuclear PKC{delta} regulates DNA-damage induced cell death is poorly understood. Here we show that PKC{delta} regulates histone modification, chromatin accessibility, and double stranded break (DSB) repair through a mechanism that requires SIRT6. Overexpression of PKC{delta} promotes genomic instability and increases DNA damage and apoptosis. Conversely, depletion of PKC{delta} increases DNA repair via non-homologous end joining (NHEJ) and homologous recombination (HR) as evidenced by more rapid formation of NHEJ (DNA-PK) and HR (Rad51) DNA damage foci, increased expression of repair proteins, and increased repair of NHEJ and HR fluorescent reporter constructs. Nuclease sensitivity indicates that PKC{delta} depletion is associated with more open chromatin, while overexpression of PKC{delta} reduces chromatin accessibility. Epiproteome analysis revealed that PKC{delta} depletion increases chromatin associated H3K36me2, and reduces ribosylation of KDM2A and chromatin bound KDM2A. We identify SIRT6 as a downstream mediator of PKC{delta}. PKC{delta}-depleted cells have increased expression of SIRT6, and depletion of SIRT6 reverses the changes in chromatin accessibility, histone modification and NHEJ and HR DNA repair seen with PKC{delta}-depletion. Furthermore, depletion of SIRT6 reverses radioprotection in PKC{delta}-depleted cells. Our studies describe a novel pathway whereby PKC{delta} orchestrates SIRT6- dependent changes in chromatin accessibility to increase DNA repair, and define a mechanism for regulation of radiation-induced apoptosis by PKC{delta}. One Sentence SummaryProtein kinase C delta modifies chromatin structure via SIRT6 to regulate DNA repair.

molecular biology↗

bioRxiv2018

Biophysical and physiological causes of coral reef microbialization

Coral reefs are declining globally as their primary producer communities shift from stony coral to fleshy macroalgae dominance. Previously, we have shown that the rise of fleshy macroalgae produces dissolved organic carbon (DOC) that lead to microbialization and coral death. Here we test the hypothesis that the biophysical cause of bacterial biomass accumulation is a relative decrease in electron acceptors relative to electron donors due to O2 loss from macroalgae. We show that 37 % of photosynthetic O2 produced by reef fleshy macroalgae is lost in the form of gas through ebullition from algae surfaces. O2 loss increases DOC:O2 ratios, decoupling the photosynthetically fixed carbon from oxidative potential for respiration. This biogeochemical environment drives heterotrophic microbes to increase cell-specific DOC consumption and cell sizes, accumulating biomass. In contrast, corals do not lose oxygen and support the growth of smaller and fewer bacteria. In situ biomass and metagenomic analyses of 87 reefs across the Pacific and Caribbean show that on algae-dominated reefs bacteria accumulate organic carbon through a Warburg-like increase in aerobic glycolytic metabolism. Because of its biophysical basis, microbialization is predicted to occur in other marine ecosystems shifting primary producer assemblages, such as planktonic communities in warming and acidifying conditions.

ecology↗

bioRxiv2018

Relevance of coral geometry in the outcomes of the coral-algal benthic war

Corals have built reefs on the benthos for millennia, becoming an essential element in marine ecosystems. Climate change and human impact, however, are favoring the invasion of non-calcifying benthic algae and reducing coral coverage. Corals rely on energy derived from photosynthesis and heterotrophic feeding, which depends on their surface area, to defend their outer perimeter. But the relation between geometric properties of corals and the outcome of competitive coral-algal interactions is not well known. To address this, 50 coral colonies interacting with algae were sampled in the Caribbean island of Curacao. 3D and 2D digital models of corals were reconstructed to measure their surface area, perimeter, and polyp sizes. A box counting algorithm was applied to calculate their fractal dimension. The perimeter and surface dimensions were statistically non-fractal, but differences in the mean surface fractal dimension captured relevant features in the structure of corals. The mean fractal dimension and surface area were negatively correlated with the percentage of losing perimeter and positively correlated with the percentage of winning perimeter. The combination of coral perimeter, mean surface fractal dimension, and coral species explained 19% of the variability of losing regions, while the surface area, perimeter, and perimeter-to-surface area ratio explained 27% of the variability of winning regions. Corals with surface fractal dimensions smaller than two and small perimeters displayed the highest percentage of losing perimeter, while corals with large surface areas and low perimeter-to-surface ratios displayed the largest percentage of winning perimeter. This study confirms the importance of fractal surface dimension, surface area, and perimeter of corals in coral-algal interactions. In combination with non-geometrical measurements such as microbial composition, this approach could facilitate environmental conservation and restoration efforts on coral reefs.

ecology↗