Colette Dehay#, Wieland Huttner# Development and evolution of the primate neocortex from a progenitor cell perspective. Development, 151(4) Art. No. dev199797 (2024) DOI
The generation of neurons in the developing neocortex is a major determinant of neocortex size. Crucially, the increase in cortical neuron numbers in the primate lineage, notably in the upper-layer neurons, contributes to increased cognitive abilities. Here, we review major evolutionary changes affecting the apical progenitors in the ventricular zone and focus on the key germinal zone constituting the foundation of neocortical neurogenesis in primates, the outer subventricular zone (OSVZ). We summarize characteristic features of the OSVZ and its key stem cell type, the basal (or outer) radial glia. Next, we concentrate on primate-specific and human-specific genes, expressed in OSVZ-progenitors, the ability of which to amplify these progenitors by targeting the regulation of the cell cycle ultimately underlies the evolutionary increase in upper-layer neurons. Finally, we address likely differences in neocortical development between present-day humans and Neanderthals that are based on human-specific amino acid substitutions in proteins operating in cortical progenitors.
Robert G. Parton#, Kai Simons# The Biology of Lipids. Cold Spring Harb Perspect Biol, Art. No. doi: 10.1101/cshperspect.a041713 (2024) DOI
Lipids are the defining features of cellular membranes. They act collectively to form a variety of different structures, and understanding their complex behavior represents an early example of systems biology. A multidisciplinary approach is needed to analyse the functions of lipids in biological systems, and new work is providing fascinating insights into their roles in membrane biology, metabolism, signaling, subcellular dynamics and various disease processes.
Dilan Martínez-Torres✳︎, Valentina Maldonado✳︎, Cristian Pérez-Gallardo, Rodrigo Yañez, Valeria Candia, Yannis Kalaidzidis, Marino Zerial, Hernán Morales-Navarrete#, Fabián Segovia-Miranda# Phenotypic characterization of liver tissue heterogeneity through a next-generation 3D single-cell atlas. Sci Rep, 14(1) Art. No. 2823 (2024)
Open Access DOI
Three-dimensional (3D) geometrical models are potent tools for quantifying complex tissue features and exploring structure-function relationships. However, these models are generally incomplete due to experimental limitations in acquiring multiple (> 4) fluorescent channels in thick tissue sections simultaneously. Indeed, predictive geometrical and functional models of the liver have been restricted to few tissue and cellular components, excluding important cellular populations such as hepatic stellate cells (HSCs) and Kupffer cells (KCs). Here, we combined deep-tissue immunostaining, multiphoton microscopy, deep-learning techniques, and 3D image processing to computationally expand the number of simultaneously reconstructed tissue structures. We then generated a spatial single-cell atlas of hepatic architecture (Hep3D), including all main tissue and cellular components at different stages of post-natal development in mice. We used Hep3D to quantitatively study 1) hepatic morphodynamics from early post-natal development to adulthood, and 2) the effect on the liver's overall structure when changing the hepatic environment after removing KCs. In addition to a complete description of bile canaliculi and sinusoidal network remodeling, our analysis uncovered unexpected spatiotemporal patterns of non-parenchymal cells and hepatocytes differing in size, number of nuclei, and DNA content. Surprisingly, we found that the specific depletion of KCs results in morphological changes in hepatocytes and HSCs. These findings reveal novel characteristics of liver heterogeneity and have important implications for both the structural organization of liver tissue and its function. Our next-gen 3D single-cell atlas is a powerful tool to understand liver tissue architecture, opening up avenues for in-depth investigations into tissue structure across both normal and pathological conditions.
Tobias Jumel#, Andrej Shevchenko# Multispecies Benchmark Analysis for LC-MS/MS Validation and Performance Evaluation in Bottom-Up Proteomics. J Proteome Res, 23(2) 684-691 (2024)
Open Access DOI
We present an instrument-independent benchmark procedure and software (LFQ_bout) for the validation and comparative evaluation of the performance of LC-MS/MS and data processing workflows in bottom-up proteomics. The procedure enables a back-to-back comparison of common and emerging workflows, e.g., diaPASEF or ScanningSWATH, and evaluates the impact of arbitrary and inadequately documented settings or black-box data processing algorithms. It enhances the overall performance and quantification accuracy by recognizing and reporting common quantification errors.
Fernando Moreto, Jéssica Leite Garcia, Ana Lúcia Dos Anjos Ferreira, Silvia Radrezza, Mariane Róvero Costa, Guilherme Ribeiro Romualdo, Nubia Alves Grandini, Giancarlo Aldini, Camila Renata Correa, Alfonsina D'Amato Quantitative proteomics study of carnosine effect in an animal model of Western diet-induced nonalcoholic fatty liver disease. J Biochem Mol Toxicol, 38(2) Art. No. e23644 (2024) DOI
The nonalcoholic fatty liver disease (NAFLD), which is closely related to westernized dietary (WD) patterns, displays a rising epidemiological and economic burden. Since there is no pharmacological therapy approved for this disease, mechanistic studies are warranted. In this work, we investigated the action of carnosine (CAR), a natural dipeptide with several protection roles against oxidative stress in the liver of NAFLD rats. NAFLD was induced by WD-rich sugars and fat, verifying the histological evidence of steatosis. As intraperitoneal administration of CAR reversed liver steatosis, the protein profiles of NAFLD liver and CAR NAFLD liver were evaluated by label-free proteomics approach. A total of 2531 proteins were identified and the 230 and 276 were significantly up- and downregulated, respectively, by CAR treatment of NAFLD rats and involved in fundamental pathways such as oxidative stress and lipid metabolism. Perilipin 2 and apolipoprotein E, components of the plasma membrane of vesicle, resulted in highly downregulated in the CAR-treated NAFLD liver. The advanced bioanalytical approach demonstrated the efficacy of CAR in overcoming the main symptoms of NAFLD, ameliorating the steatosis in the liver.
Christopher Schmied#, Michael S Nelson, Sergiy Avilov, Gert-Jan Bakker, Cristina Bertocchi, Johanna Bischof, Ulrike Boehm, Jan Brocher, Mariana T Carvalho, Catalin Chiritescu, Jana Christopher, Beth A Cimini, Eduardo Conde-Sousa, Michael Ebner, Rupert Ecker, Kevin W Eliceiri, Julia Fernandez-Rodriguez, Nathalie Gaudreault, Laurent Gelman, David Grunwald, Tingting Gu, Nadia Halidi, Mathias Hammer, Matthew Hartley, Michael Held, Florian Jug, Varun Kapoor, Ayse Aslihan Koksoy, Judith Lacoste, Sylvia Le Dévédec, Sylvie Le Guyader, Penghuan Liu, Gabriel G Martins, Aastha Mathur, Kyoko Miura, Paula Montero Llopis, Roland Nitschke, Alison J North, Adam C Parslow, Alex Payne-Dwyer, Laure Plantard, Rizwan Ali, Britta Schroth-Diez, Lucas Schütz, Ryan T Scott, Arne Seitz, Olaf Selchow, Ved P Sharma, Martin Spitaler, Sathya Srinivasan, Caterina Strambio-De-Castillia, Dylan J Taatjes, Christian Tischer#, Helena Jambor# Community-developed checklists for publishing images and image analyses. Nat Methods, 21(2) 170-181 (2024) DOI
Images document scientific discoveries and are prevalent in modern biomedical research. Microscopy imaging in particular is currently undergoing rapid technological advancements. However, for scientists wishing to publish obtained images and image-analysis results, there are currently no unified guidelines for best practices. Consequently, microscopy images and image data in publications may be unclear or difficult to interpret. Here, we present community-developed checklists for preparing light microscopy images and describing image analyses for publications. These checklists offer authors, readers and publishers key recommendations for image formatting and annotation, color selection, data availability and reporting image-analysis workflows. The goal of our guidelines is to increase the clarity and reproducibility of image figures and thereby to heighten the quality and explanatory power of microscopy data.
Nagaraja Chappidi, Thomas Quail, Simon Doll, Laura T Vogel, Radoslav Aleksandrov, Suren Felekyan, Ralf Kühnemuth, Stoyno Stoynov, Claus A M Seidel, Jan Brugués, Marcus Jahnel, Titus Franzmann, Simon Alberti PARP1-DNA co-condensation drives DNA repair site assembly to prevent disjunction of broken DNA ends. Cell, Art. No. doi: 10.1016/j.cell.2024.01.015 (2024)
Open Access DOI
DNA double-strand breaks (DSBs) are repaired at DSB sites. How DSB sites assemble and how broken DNA is prevented from separating is not understood. Here we uncover that the synapsis of broken DNA is mediated by the DSB sensor protein poly(ADP-ribose) (PAR) polymerase 1 (PARP1). Using bottom-up biochemistry, we reconstitute functional DSB sites and show that DSB sites form through co-condensation of PARP1 multimers with DNA. The co-condensates exert mechanical forces to keep DNA ends together and become enzymatically active for PAR synthesis. PARylation promotes release of PARP1 from DNA ends and the recruitment of effectors, such as Fused in Sarcoma, which stabilizes broken DNA ends against separation, revealing a finely orchestrated order of events that primes broken DNA for repair. We provide a comprehensive model for the hierarchical assembly of DSB condensates to explain DNA end synapsis and the recruitment of effector proteins for DNA damage repair.
Kathrin Schmeisser#, Damla Kaptan, Bharath Kumar Raghuraman, Andrej Shevchenko, Jonathan Rodenfels, Sider Penkov, Teymuras V. Kurzchalia# Mobilization of cholesterol induces the transition from quiescence to growth in Caenorhabditis elegans through steroid hormone and mTOR signaling. Commun Biol, 7(1) Art. No. 121 (2024)
Open Access DOI
Recovery from the quiescent developmental stage called dauer is an essential process in C. elegans and provides an excellent model to understand how metabolic transitions contribute to developmental plasticity. Here we show that cholesterol bound to the small secreted proteins SCL-12 or SCL-13 is sequestered in the gut lumen during the dauer state. Upon recovery from dauer, bound cholesterol undergoes endocytosis into lysosomes of intestinal cells, where SCL-12 and SCL-13 are degraded and cholesterol is released. Free cholesterol activates mTORC1 and is used for the production of dafachronic acids. This leads to promotion of protein synthesis and growth, and a metabolic switch at the transcriptional level. Thus, mobilization of sequestered cholesterol stores is the key event for transition from quiescence to growth, and cholesterol is the major signaling molecule in this process.
Priyanka Bhatia, Marc Bickle, Amay A Agrawal, Buster Truss, Aikaterina Nikolaidi, Kathrin Brockmann, Lydia Reinhardt, Stefanie Vogel, Eva M Szegoe, Arun Pal, Andreas Hermann, Ivan Mikicic, Maximina H Yun, Björn H Falkenburger, Jared Sterneckert Axonal Lysosomal Assays for Characterizing the Effects of LRRK2 G2019S. Biology (Basel), 13(1) Art. No. 58 (2024)
Open Access DOI
The degeneration of axon terminals before the soma, referred to as "dying back", is a feature of Parkinson's disease (PD). Axonal assays are needed to model early PD pathogenesis as well as identify protective therapeutics. We hypothesized that defects in axon lysosomal trafficking as well as injury repair might be important contributing factors to "dying back" pathology in PD. Since primary human PD neurons are inaccessible, we developed assays to quantify axonal trafficking and injury repair using induced pluripotent stem cell (iPSC)-derived neurons with LRRK2 G2019S, which is one of the most common known PD mutations, and isogenic controls. We observed a subtle axonal trafficking phenotype that was partially rescued by a LRRK2 inhibitor. Mutant LRRK2 neurons showed increased phosphorylated Rab10-positive lysosomes, and lysosomal membrane damage increased LRRK2-dependent Rab10 phosphorylation. Neurons with mutant LRRK2 showed a transient increase in lysosomes at axotomy injury sites. This was a pilot study that used two patient-derived lines to develop its methodology; we observed subtle phenotypes that might correlate with heterogeneity in LRRK2-PD patients. Further analysis using additional iPSC lines is needed. Therefore, our axonal lysosomal assays can potentially be used to characterize early PD pathogenesis and test possible therapeutics.
Jana Karbanová✳︎, Ilker A Deniz✳︎, Michaela Wilsch-Bräuninger, Rita Alexandra de Sousa Couto, Christine A. Fargeas, Mark F Santos, Aurelio Lorico#, Denis Corbeil# Extracellular lipidosomes containing lipid droplets and mitochondria are released during melanoma cell division. Cell Commun Signal, 22(1) Art. No. 57 (2024)
Open Access DOI
The incidence of melanoma is increasing worldwide. Since metastatic melanoma is highly aggressive, it is important to decipher all the biological aspects of melanoma cells. In this context, we have previously shown that metastatic FEMX-I melanoma cells release small (< 150 nm) extracellular vesicles (EVs) known as exosomes and ectosomes containing the stem (and cancer stem) cell antigenic marker CD133. EVs play an important role in intercellular communication, which could have a micro-environmental impact on surrounding tissues.