Biology subjects

Maimon, R.

Publications and source records attributed to Maimon, R..

6 recordsLinked to original sources

bioRxiv2026

MERFISHEYES: Web-based Visualization and Sharing Platform for Single-cell and Single-molecule Spatial Transcriptomics

Interactive exploration and sharing of hybridization-based spatial transcriptomics datasets remain limited by large file sizes, specialized software, and computationally intensive preprocessing, restricting rapid access to publicly available resources such as the Brain Image Library. Here we present MERFISHEYES (https://merfisheyes.com), a browser-based platform for interactive visualization of single-cell and single-molecule spatial transcriptomics data across commercial and emerging high-throughput platforms. MERFISHEYES enables marker gene exploration, cross-dataset and cross-species comparison, visualization of subcellular RNA localization, and collaborative sharing through browser-accessible links generated directly from drag-and-drop datasets. We use MERFISHEYES to enable browser-based visualization of all 158 spatial transcriptomics datasets in the Brain Image Library and demonstrate its capabilities in handling high-throughput 3D data with genome-scale imputation of gene expression and DNA accessibility. MERFISHEYES provides a scalable framework for rapid exploration, sharing, and collaborative analysis of spatial transcriptomics data.

bioinformatics↗

bioRxiv2025

Multimodal spatial transcriptomics determines repeat expansion, huntingtin aggregation, and selective cortical neuron loss in Huntington Disease

Huntingtons disease (HD) is caused by CAG expansion in HTT, yet how somatic repeat instability and huntingtin aggregation relate to selective cell loss in the human brain remains unclear. We have developed a multimodal spatial transcriptomics approach that enables defining transcriptional programs with subcellular resolution, somatic CAG repeat lengths, and six other pathology marks including huntingtin aggregates in every cell of intact brain sections. Imaging 428,173 cells in HD cortex revealed selective vulnerability: L5-6 NP and L6b deep-layer excitatory neurons undergo >50% loss, closely linked to very large (>380{+/-}55) somatic expansions. Intranuclear aggregation was most prevalent at intermediate somatic repeat expansion (220-300 CAGs) and was accompanied by broader transcriptional changes. In contrast, chandelier and somatostatin+ inhibitory interneurons are lost despite only modest repeat expansion or aggregation. These data provide a comprehensive resource and establish a broadly applicable framework for connecting repeat expansion and protein pathology across diverse cell types. Short Bullet pointsO_LIDevelopment of a novel, multimodal spatial transcriptomics platform enables definition of RNA transcriptomes with subcellular resolution, somatic repeat expansions, and protein accumulation in cells within tissue sections C_LIO_LIGeneration of two complementary datasets for HD and control cortex: 428,173 cells to quantify comprehensively cell-type vulnerability, and a deeper multimodal dataset in which CAG repeat expansion, huntingtin aggregation, six additional pathological readouts, and expression of 1,128 genes were measured in 185,721 cells, providing a comprehensive resource for the neurodegeneration community. C_LIO_LIDeep layer excitatory neuron loss (L5-6 NP and L6b) was associated with very large somatic CAG expansions (>380{+/-}55), while selective inhibitory neuron loss (chandelier and somatostatin interneurons) occurred with modest CAG repeat expansion or huntingtin intranuclear aggregation C_LIO_LIIntranuclear aggregation, not somatic repeat expansion, was more predictive of transcriptional changes, including chromatin remodeling and RNA export factors C_LI

neuroscience↗

bioRxiv2024

Re-activation of neurogenic niches in aging brain

Recent studies proposing induced glia-to-neuron conversion raised the potential for generating new neurons to replace those lost due to injury, aging or neurodegenerative diseases. Here, single-cell spatial transcriptomics [Multiplexed Error Robust Fluorescence In Situ Hybridization (MERFISH)] is used to construct a spatial cell atlas of the subventricular and dentate gyrus neurogenic niches of young and aged adult murine brain. RNAs that encode the RNA binding protein Polypyrimidine Tract-Binding Protein (PTBP1) in the aged murine brain are determined to be highest in glia that line previously active neurogenic niches. A glial cell population with ependymal character within an initially quiescent subventricular neurogenic niche in the aged murine brain is identified that upon transient suppression of PTBP1 reenters the cell cycle, replicates DNA, and converts into neurons through a canonical adult neurogenesis pathway. Glia-derived neurons migrate from this niche, with some neurons transiting to the striatum and acquiring a transcriptome characteristic of GABAergic inhibitory neurons. Similar PTBP1 expressing quiescent glia are identified in the corresponding neurogenic niche of aged human brain. Thus, transient reduction of PTBP1 holds potential for inducing the generation of new neurons in quiescent neurogenic niches of the aged nervous system, thereby offering promising therapeutic applications. Bullet point summary1) Single-cell spatial transcriptomics is used to validate active neurogenesis in the two neurogenic niches of the young adult murine brain, determine that those niches are quiescent in the aging adult brain of mice, and demonstrate the absence of neurogenesis in the aging human brain. 2) The RNA binding protein PTBP1 is determined to be most highly expressed within glia that line the aged murine and human neurogenic niches, with its transient reduction sufficient in mice to activate/re-activate expression of genes characteristic of immature neurons. 3) Suppression of PTBP1 using a single intra-cerebral-ventricular injection of PTBP1-targeting antisense oligonucleotide (ASO) induces generation of new immature neurons in the neurogenic niches of the aged mouse brain via a canonical adult neurogenesis pathway. 4) Single-cell RNA signature tracing is used to identify a) a subclass of ependymal cells in a previously quiescent neurogenic niche of the aged mouse brain that convert into GABAergic inhibitory neurons following transient suppression of PTBP1, and b) the molecular steps in the conversion process including cell cycle re-entry, DNA replication, and transcriptome changes that mimic canonical neurogenesis. 5) A similar class of PTBP1-expressing ependymal cells lining the ventricle of the aging non-human primate and human brains is identified, suggesting the promise of re-activation of neurogenesis as a therapeutic approach in humans.

neuroscience↗

bioRxiv2023

Aberrant splicing in Huntington's disease via disrupted TDP-43 activity accompanied by altered m6A RNA modification.

Huntingtons disease (HD) is a neurodegenerative disorder caused by a CAG repeat expansion in the first exon of the HTT gene encoding huntingtin. Prior reports have established a correlation between CAG expanded HTT and altered gene expression. However, the mechanisms leading to disruption of RNA processing in HD remain unclear. Here, our analysis of the reported HTT protein interactome identifies interactions with known RNA-binding proteins (RBPs). Total, long-read sequencing and targeted RASL-seq of RNAs from cortex and striatum of the HD mouse model R6/2 reveals increased exon skipping which is confirmed in Q150 and Q175 knock-in mice and in HD human brain. We identify the RBP TDP-43 and the N6-methyladenosine (m6A) writer protein methyltransferase 3 (METTL3) to be upstream regulators of exon skipping in HD. Along with this novel mechanistic insight, we observe decreased nuclear localization of TDP-43 and cytoplasmic accumulation of phosphorylated TDP-43 in HD mice and human brain. In addition, TDP-43 co-localizes with HTT in human HD brain forming novel nuclear aggregate-like bodies distinct from mutant HTT inclusions or previously observed TDP-43 pathologies. Binding of TDP-43 onto RNAs encoding HD-associated differentially expressed and aberrantly spliced genes is decreased. Finally, m6A RNA modification is reduced on RNAs abnormally expressed in striatum from HD R6/2 mouse brain, including at clustered sites adjacent to TDP-43 binding sites. Our evidence supports TDP-43 loss of function coupled with altered m6A modification as a novel mechanism underlying alternative splicing/unannotated exon usage in HD and highlights the critical nature of TDP-43 function across multiple neurodegenerative diseases.

neuroscience↗

bioRxiv2019

Sema3A Facilitates a Retrograde Death Signal via CRMP4-Dynein Complex Formation in ALS Motor Axons

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease with selective dysfunction; it causes the death of motor neurons (MNs). In spite of some progress, currently no effective treatment is available for ALS. Before such treatment can be developed, a more thorough understanding of ALS pathogenesis is required. Recently, we demonstrated that ALS-mutated muscles contribute to ALS pathology via secretion of destabilizing factors such as Sema3A; these factors trigger axon degeneration and Neuromuscular Junction (NMJ) disruption. Here, we focus on the molecular mechanism by which muscle contribute to MNs loss in ALS. We identified CRMP4 as part of a retrograde death signal generated in response to muscle-secreted Sema3A, in ALS-diseased MNs. Exposing distal axons to Sema3A induces CRMP4-dynein complex formation and MN loss in both mouse (SOD1G93A) and human-derived (C9orf72) ALS models. Introducing peptides that interfere with CRMP4-dynein interaction in MN axons profoundly reduces Sema3A-dependent MN loss. Thus, we discovered a novel retrograde death signal mechanism underlying MN loss in ALS.\n\nSummaryMaimon et al. identify a novel retrograde death mechanism that contribute to MN loss in ALS, in which CRMP4-Dynein complex is form and retrogradely move along the axon.

neuroscience↗

bioRxiv2019

CRMP2 mediates Sema3F-dependent axon pruning and dendritic spine remodeling

Regulation of axon guidance and pruning of inappropriate synapses by class 3 semaphorins is key to development of neural circuits. Collapsin response mediator protein 2 (CRMP2) has been shown to regulate axon guidance by mediating Semaphorin 3A (Sema3A) signaling and its dysfunction has been linked to schizophrenia, however, nothing is known about its role in the synapse pruning. Here, using newly generated crmp2-/- mice we demonstrate that while CRMP2 has only a moderate effect on Sema3A-dependent axon guidance in vivo, it is essential for Sema3F-dependent axon pruning and dendritic spine remodeling. We first demonstrate that CRMP2 deficiency interferes with Sema3A signaling in compartmentalized neuron cultures and leads to a mild defect in axon guidance in peripheral nerves and corpus callosum. Strikingly, we show that crmp2-/- mice display more prominent defects in dendritic spine pruning and stereotyped axon pruning in hippocampus and visual cortex consistent with impaired Sema3F signaling and with autism spectrum disorder (ASD)-rather than schizophrenia-like phenotype. Indeed, we demonstrate that CRMP2 mediates Sema3F-induced axon retraction in primary neurons and that crmp2-/- mice display early postnatal behavioral changes linked to ASD. In conclusion, we demonstrate that CRMP2 is an essential mediator of Sema3F-dependent synapse pruning and its dysfunction in early postnatal stages shares histological and behavioral features of ASD.

neuroscience↗