Biology subjects

Corbat, A. A.

Publications and source records attributed to Corbat, A. A..

6 recordsLinked to original sources

bioRxiv2026

In utero barcoding of mouse mesoderm reveals the clonal architecture of organ mesenchyme

The mesoderm coordinates organogenesis and generates the cardiovascular, visceral and musculoskeletal systems, yet in mammals this germ layer is difficult to access, impeding its genetic manipulation and study. Here, we establish embryonic day (E) 7.5 exocoelomic cavity nano-injection as a scalable route for selective genetic targeting of mouse mesoderm. Combining in utero lentiviral barcoding with single-cell and spatial transcriptomics, we reconstructed mesodermal and neural crest clonal relationships across >590,000 cells and 31,000 multicellular clones from E9.5-E10.5 embryos and E16.5 livers and hearts. In liver, capsular mesothelium was closely related to hepatic stellate cells, whereas fibroblast and vascular smooth muscle lineages diverged earlier. In heart, epicardium was clonally coupled to three spatially restricted mesenchymal sub-lineages but not to cardiomyocytes, and lineage tracing separated epicardial- and neural crest-derived populations within transcriptionally convergent valve mesenchyme. This approach enables Cre-independent manipulation of mammalian mesoderm and resolves organ mesenchyme development at clonal resolution.

developmental biology↗

bioRxiv2026

AI4Life Open Calls and Public Challenges: why, how, and what we have learned.

Within AI4Life, we ran three Open Calls and three Public Challenges (2023-2025), supporting 22 bioimage analysis projects from 151 applications and engaging 225 challenge participants, with the aim of applying FAIR deep learning in the life sciences. Our experience offers a view of the current state of bioimage analysis, the landscape of available tools, as well as the existing gaps between method developers, tool producers and potential users. It highlights that even after careful selection for AI-ready projects, most still require substantial effort to apply deep learning, and that the field still relies heavily on established, well-rounded methods to solve common problems. We come to the conclusion that for scientific AI in biology, the rate-limiting step is not methods and models but data, annotations, and shared infrastructure underneath them.

bioinformatics↗

bioRxiv2024

Jag1 represses Notch activation in lateral supporting cells and inhibits an outer hair cell fate in the medial compartment of the developing cochlea

Notch signaling regulates both inner and middle ear morphogenesis and establishes a strict pattern of sensory cells in the organ of Corti in the mammalian cochlea. Patients with Alagille syndrome have impaired Notch signaling ([~]94% with JAG1 mutations) resulting in sensorineural and conductive hearing loss. Here, we investigate the function of Jag1-mediated Notch activation in cochlear patterning and signaling using the Jag1 "Nodder" (Jag1Ndr/Ndr) mouse model of Alagille syndrome. Jag1Ndr/Ndr mice exhibited severe vestibular and auditory deficits and a dose-dependent increase in ectopic inner hair cells and a reduction in outer hair cells. Single cell RNA sequencing of the organ of Corti demonstrated a global dysregulation of genes associated with inner ear development and deafness. Analysis of individual cell types indicated a novel role for Jag1 in repressing Notch activation in lateral supporting cells and revealed a function for Jag1 in gene regulation and development of outer hair cells. Additionally, "outer hair cell-like" SLC26A5 (Prestin) positive cells were present in the medial compartment and pillar cell region of Jag1Ndr/Ndr mice and exhibited location-dependent expression of the inner hair cell fate-regulator Tbx2, revisiting the potency of Tbx2 in driving inner hair cell commitment in "outer hair cell-like" cells in the Jag1-mutant IHC compartment. Our data reveals a novel role for Jag1 in repressing Notch activation in lateral supporting cells and highlights involvement for Notch signaling in inner versus outer hair cell specification and positioning.

developmental biology↗

bioRxiv2021

An Integrative Apoptotic Reaction Model for extrinsic and intrinsic stimuli

Apoptosis, a form of programmed cell death central to all multicellular organisms, plays a key role during organism development and is often misregulated in cancer. Devising a single model applicable to distinct stimuli and conditions has been limited by lack of robust observables. Indeed, previous numerical models have been tailored to fit experimental datasets in restricted scenarios, failing to predict response to different stimuli. We quantified the activity of three caspases simultaneously upon intrinsic or extrinsic stimulation to assemble a comprehensive dataset. We measured and modeled the time between maximum activity of intrinsic, extrinsic and effector caspases, a robust observable of network dynamics, to create the first integrated Apoptotic Reaction Model (ARM). Observing how effector caspases reach maximum activity first irrespective of stimuli used, led us to identify and incorporate a missing feedback into a successful model for extrinsic stimulation. By simulating different recently performed experiments, we corroborated that ARM adequately describes them. This integrated model provides further insight into the indispensable feedback from effector caspase to initiator caspases.

systems biology↗

bioRxiv2021

CASPAM: a triple modality biosensor for multiplexed imaging of caspase network activity

Understanding signal propagation across biological networks requires to simultaneously monitor the dynamics of several nodes to uncover correlations masked by inherent intercellular variability. To monitor the enzymatic activity of more than two components over short time scales has proven challenging. Exploiting the narrow spectral width of homoFRET-based biosensors, up to three activities can be imaged through fluorescence polarization anisotropy microscopy. We introduce CASPAM (Caspase Activity Sensor by Polarization Anisotropy Multiplexing) a single-plasmid triple-modality-reporter of key nodes of the apoptotic network. Apoptosis provides an ideal molecular framework to study interactions between its three composing pathways (intrinsic, extrinsic and effector). We characterized the biosensor performance and demonstrated the advantages that equimolar expression has both in simplifying experimental procedure and reducing observable variation, thus enabling robust data-driven modelling. Tools like CASPAM become essential to analyze molecular pathways where multiple nodes need to be simultaneously monitored.

cell biology↗

bioRxiv2020

Smaug membraneless organelles regulate mitochondrial function

Smaug is a conserved translational repressor that recognizes specific RNA motifs in a large number of mRNAs, including nuclear transcripts that encode mitochondrial enzymes. Smaug orthologs have been shown to form membraneless organelles (MLOs) in several organisms and cell types. Using single-molecule FISH we show here that SDHB and UQCRC1 mRNAs associate with Smaug1 MLOs in the human cell line U2OS. Simultaneous loss of function of Smaug1 and Smaug2 affects both mitochondrial respiration and mitochondrial network morphology. Deletion of specific Smaug1 protein regions resulted in impaired MLO formation that correlates with mitochondrial defects. In addition, rotenone but not the respiratory chain uncoupling agent CCCP rapidly induces Smaug1 MLO dissolution. Finally, metformin elicits a similar effect on Smaug1 MLOs and provokes the release of bounded mRNAs. We propose that mitochondrial activity affects Smaug1 MLO dynamics, thus allowing for regulation of nuclear mRNAs that encode key mitochondrial proteins.

cell biology↗