Biology subjects

Plass, M.

Publications and source records attributed to Plass, M..

6 recordsLinked to original sources

bioRxiv2025

Staufen2 modulates the temporal dynamics of human neurogenesis in vitro

RNA-binding proteins (RBPs) play a central role in post-transcriptional regulation during brain development, yet their specific functions in coordinating human neural lineage decisions remain poorly understood. Here, we investigate for the first time the role of the double-stranded RBP Staufen2 (STAU2) in human neurogenesis. Characterization of STAU2 knockout iPSC derived cells using scRNA-seq shows that loss of STAU2 disrupts neuroepithelial cell identity and accelerates neural differentiation by altering the activity of key transcription factors and driving early metabolic transitions. Additionally, STAU2 regulates the expression of miRNA host genes and alters miRNA-mediated post- transcriptional control in progenitor cells, which exerts additional effects on STAU2 regulated gene regulatory networks. These changes result in neural progenitor exhaustion, unstructured neural rosettes, and reduced organoid size. Together, our work uncovers a previously unrecognized role for STAU2 as a central regulator of early human neurogenesis, acting through both miRNA-mediated and transcriptional pathways to coordinate progenitor maintenance and neuronal fate specification.

molecular biology↗

bioRxiv2025

Astrocytic Ceruloplasmin Deficiency Triggers Iron Toxicity and Neurodegeneration in a LRRK2 Parkinson's Tri-Culture Model

Astrocytes and microglia carrying the LRRK2-G2019S mutation contribute to non-cell- autonomous dopaminergic neuron (DAn) degeneration in Parkinsons disease (PD), but the mechanisms underlying their interplay remain unclear. Here, we developed a novel induced pluripotent stem cell (iPSC)-derived tri-culture system comprising healthy DAn and either LRRK2-mutant or isogenic control iPSC-derived astrocytes and microglia. Using integrated functional assays and transcriptomic profiling, we found that mutant astrocytes adopt a hyperreactive state, driving microglial activation and subsequent DAn degeneration. Mechanistically, we identified a selective downregulation of ceruloplasmin (CP), a copper-dependent ferroxidase, in mutant astrocytes, leading to disrupted iron homeostasis with accumulation of Fe2+ and ROS. This iron dysregulation mediated both microglial reactivity and neurodegeneration. Notably, pharmacological restoration of CP re-established iron homeostasis, reduced microglial activation, and protected DAn from degeneration. Our findings uncover a novel astrocyte-microglia-neuron axis driving PD pathogenesis and showcase the power of our unique stem cell tri-culture platform for dissecting disease mechanisms and discovering therapeutic targets.

cell biology↗

bioRxiv2024

Quantification of transcript isoforms at the single-cell level using SCALPEL

Single-cell RNA sequencing (scRNA-seq) has facilitated the study of gene expression and the development of new tools to quantify transcript in individual cells. Yet, most of these methods have low sensitivity and accuracy. Here we present SCALPEL, a Nextflow-based tool to quantify and characterize transcript isoforms at the single-cell level using standard 3 based scRNA-seq data. SCALPEL predictions have higher sensitivity than other tools and can be validated experimentally. We have used SCALPEL to study the changes in isoform usage during mouse spermatogenesis and in the differentiation of induced pluripotent stem cells (iPSCs) to neural progenitors. These analyses allow the identification of novel cell populations that cannot be defined using conventional gene expression profiles, confirm known changes in 3 UTR length during cell differentiation, and identify cell-type specific miRNA signatures controlling isoform expression in individual cells. Together, our work highlights how SCALPEL expands the current scRNA-seq toolset to explore post-transcriptional gene regulation in individual cells from different species, tissues, and technologies to investigate the variability and the specificity of gene regulatory mechanisms at the single-cell level.

bioinformatics↗

bioRxiv2022

Methanol fixation is the method of choice for droplet-based single-cell transcriptomics of neural cells

Single-cell transcriptomics methods have become very popular to study the cellular composition of organs and tissues and characterize the expression profiles of the individual cells that compose them. The main critical step in single-cell transcriptomics is sample preparation. Several methods have been developed to preserve cells after sample dissociation to uncouple sample handling from library preparation. Yet, the suitability of these methods depends on the types of cells to be processed. In this project, we perform a systematic comparison of preservation methods for droplet-based single-cell RNA-seq (scRNA-seq) on neural and glial cells derived from induced pluripotent stem cells (iPSCs) and highlight their strengths and weaknesses. We compared the cellular composition and expression profile of single-cell suspensions from fresh NPCs with that of NPCs preserved with Dimethyl Sulfoxide (DMSO), Methanol, vivoPHIX and Acetil-methanol (ACME). Our results show that while DMSO provides the highest cell quality in terms of RNA molecules and genes detected per cell, it strongly affects the cellular composition and the expression profile of the resulting datasets. In contrast, methanol fixed samples display a cellular composition like that of fresh samples while providing a good cell quality and smaller expression biases. Taken together, our results show that methanol fixation is the method of choice for performing droplet-based single-cell transcriptomics experiments on neural cell populations.

genomics↗

bioRxiv2021

The X-linked splicing regulator MBNL3 has been co-opted to restrict placental growth in eutherians

The eutherian placenta is a major site for parental genetic conflict. Here, we identify the X-linked Mbnl3 gene as a novel player in this dispute. Mbnl3 belongs to an RNA binding protein family whose members regulate alternative splicing and other aspects of RNA metabolism in association with cellular differentiation. We find that, in eutherians, Mbnl3 has become specifically expressed in placenta and has undergone accelerated sequence evolution leading to changes in its RNA binding specificities. Although its molecular roles are partly redundant with those of Mbnl2, Mbnl3 has also acquired novel biological functions. In particular, whereas Mbnl2;Mbnl3 double knockout mice display severe placental maturation defects leading to strong histological and functional abnormalities, Mbnl3 knockout alone results in increased placental growth and favors placental and fetal resource allocation during limiting conditions.

evolutionary biology↗

bioRxiv2017

Graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells

Single-cell RNA-seq quantifies biological heterogeneity across both discrete cell types and continuous cell transitions. Partition-based graph abstraction (PAGA) provides an interpretable graph-like map of the arising data manifold, based on estimating connectivity of manifold partitions (https://github.com/theislab/paga). PAGA maps provide interpretable discrete and continuous latent coordinates for both disconnected and continuous structure in data, preserve the global topology of data, allow analyzing data at different resolutions and result in much higher computational efficiency of the typical exploratory data analysis workflow -- one million cells take on the order of a minute, a speedup of 130 times compared to UMAP. We demonstrate the method by inferring structure-rich cell maps with consistent topology across four hematopoietic datasets, confirm the reconstruction of lineage relations of adult planaria and the zebrafish embryo, benchmark computational performance on a neuronal dataset and detect a biological trajectory in one deep-learning processed image dataset.

bioinformatics↗