Biology subjects

Cwetsch, A. W.

Publications and source records attributed to Cwetsch, A. W..

6 recordsLinked to original sources

bioRxiv2026

Disease-associated variants alter a novel physiological role of hnRNP H2 in neuronal development

Heterogeneous nuclear ribonucleoprotein H2 (hnRNP H2) is a member of the hnRNP family of RNA-binding proteins that regulate neuronal function through multiple aspects of RNA metabolism. Mutations in the nuclear localisation signal (NLS) and quasi-RNA recognition motifs (qRRMs) of hnRNP H2 have recently been linked to a severe developmental syndrome, termed HNRNPH2-related neurodevelopmental disorder. Despite its emerging importance, the physiological roles of hnRNP H2 in neuronal development and synaptic maturation, and how disease-associated variants alter these processes to drive pathology, remain poorly understood. Here, we show that hnRNP H2 is expressed in hippocampal neurons and localises to the synaptic compartment. Knockdown of hnRNP H2 revealed essential roles of the protein in the regulation of neuronal morphology, dendritic spine maturation, synaptic transmission, and cortical neuronal migration in vivo. Disease-associated hnRNP H2 variants altered protein localisation and activity-dependent synaptic recruitment, resulting in defects in neuronal morphology, in vivo cortical neuronal migration and laminar orientation, dendritic spine maturation, and synaptic function. Together, these findings establish hnRNP H2 as a critical regulator of neurodevelopment and identify a molecular basis for HNRNPH2-related neurodevelopmental disorder.

neuroscience↗

bioRxiv2025

Autism and Schizophrenia-Associated Pcdh8 Regulates Cortical Development in Mice

Defective cortical development with aberrant neuronal distribution is linked to diverse human pathologies. We show that downregulation of protocadherin-8, a cell-adhesion protein associated with autism and schizophrenia, disrupts neuronal migration and morphology, and increases proliferation in the developing mouse cortex. These findings identify protocadherin-8 as a critical determinant of cortical organization and implicate it in the potential molecular mechanisms underlying human brain pathology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=157 SRC="FIGDIR/small/688622v1_ufig1.gif" ALT="Figure 1"> View larger version (58K): org.highwire.dtl.DTLVardef@1dde890org.highwire.dtl.DTLVardef@1cf69c5org.highwire.dtl.DTLVardef@293bceorg.highwire.dtl.DTLVardef@1159217_HPS_FORMAT_FIGEXP M_FIG C_FIG In briefDownregulation of Pcdh8--a cell-adhesion protein linked to autism and schizophrenia-- disrupts neuronal migration and morphology and increases proliferation in the developing mouse cortex.

neuroscience↗

bioRxiv2023

Bidirectional interaction between Protocadherin 8 and transcription factor Dbx1 regulates cerebral cortex development

Brain development requires correct tissue patterning and production of appropriate cell types. Transcription factors (TFs) play essential roles in these processes, regulating the expression of target genes responsible for neuronal subtypes specific features. Cell adhesion molecules are key components of developmental processes that control cell sorting, migration, neurite outgrowth/guidance and synaptogenesis. To date, the link between TFs and cell adhesion molecules is considered to be unidirectional. Here, we demonstrate that ectopic expression of Dbx1 leads to spatio-temporally restricted increased expression of Pcdh8 and cell aggregation, together with changes in neuronal identity. Surprisingly, Pcdh8 overexpression also induces Dbx1 expression as well as a complete reorganisation of apico-basal polarity and dorso-ventral patterning via Notch signalling. Altogether, our work therefore points to cell adhesion molecules as unexpected, yet important, players in the regulation of cell identity and, in particular, Pcdh8 through its bidirectional interaction with the Dbx1 transcription factor.

neuroscience↗

bioRxiv2020

Single-cell transcriptomics of the early developing mouse cerebral cortex disentangles the spatial and temporal components of neuronal fate acquisition

In the developing cerebral cortex, how progenitors that seemingly display limited diversity end up in producing a vast array of neurons remains a puzzling question. The prevailing model that recently emerged suggests that temporal maturation of these progenitors is a key driver in the diversification of the neuronal output. However, temporal constrains are unlikely to account for all diversity across cortical regions, especially in the ventral and lateral domains where neuronal types significantly differ from their dorsal neocortical counterparts born at the same time. In this study, we implemented single-cell RNAseq to sample the diversity of progenitors and neurons along the dorso-ventral axis of the early developing pallium. We first identified neuronal types, mapped them on the tissue and performed genetic tracing to determine their origin. By characterising progenitor diversity, we disentangled the gene expression modules underlying temporal vs spatial regulations of neuronal specification. Finally, we reconstructed the developmental trajectories followed by ventral and dorsal pallial neurons to identify gene waves specific of each lineage. Our data suggest a model by which discrete neuronal fate acquisition from a continuous gradient of progenitors results from the superimposition of spatial information and temporal maturation.

developmental biology↗

bioRxiv2020

Mosaic expression of X-linked PCDH19 Protein by in Utero Electroporation in Rats Replicates Human Cortical and Hippocampal Developmental Abnormalities, Associated Core Behaviors Related to Autism, and Cognitive Impairment.

PCDH19 gene-related epilepsy or epileptic encephalopathy, early infantile, 9 (EIEE9) is an infantile onset epilepsy syndrome characterized by psychiatric (including autistic) sensory and cognitive impairment of varying degrees. EIEE9 is caused by X-linked PCDH19 protein loss of function. Due to random X-chromosome inactivation, EIEE9-affected females present a mosaic population of healthy and Pcdh19-mutant cells. Unfortunately, no mouse models recapitulate to date both the brain histological and behavioural deficits present in people with EIEE9. Thus, the search for a proper understanding of the disease, and possible future treatment is hampered. By inducing a focal mosaicism of Pcdh19 expression using in utero electroporation in rat, we found here that Pcdh19 signaling in specific brain areas is implicated in neuronal migration, as well as in core behaviors related to autism and cognitive function.

neuroscience↗

bioRxiv2019

A Cre-amplifier to generate and detect genetic mosaics in vivo

Cre-Lox manipulation is the gold standard for cell-specific expression or knockout of selected genes. However, it is not unusual to deal with conditions of low Cre expression or transient activation, which can often go undetected by conventional Cre-reporters. We designed Beatrix, a general-purpose tool specifically devised to amplify weak Cre recombinase activity, and we used it to develop a powerful approach for the in vivo generation and detection of sparse mosaics of mutant and wild type cells.

neuroscience↗