Recent CIG publications Archive

Front Endocrinol (Lausanne).: 2023 Jan 5;13:1073759. doi: 10.3389/fendo.2022.1073759. eCollection 2022.

Ontogeny of ependymoglial cells lining the third ventricle in mice

David Lopez-Rodriguez ¹, Antoine Rohrbach ¹, Marc Lanzillo ², Manon Gervais ², Sophie Croizier ², Fanny Langlet ¹

Abstract

Introduction: During hypothalamic development, the germinative neuroepithelium gives birth to diverse neural cells that regulate numerous physiological functions in adulthood.

Methods: Here, we studied the ontogeny of ependymal cells in the mouse mediobasal hypothalamus using the BrdU approach and publicly available single-cell RNAseq datasets.

Results: We observed that while typical ependymal cells are mainly produced at E13, tanycyte birth depends on time and subtypes and lasts up to P8. Typical ependymocytes and β tanycytes are the first to arise at the top and bottom of the dorsoventral axis around E13, whereas α tanycytes emerge later in development, generating an outside-in dorsoventral gradient along the third ventricle. Additionally, α tanycyte generation displayed a rostral-to-caudal pattern. Finally, tanycytes mature progressively until they reach transcriptional maturity between P4 and P14.

Discussion: Altogether, this data shows that ependyma generation differs in time and distribution, highlighting the heterogeneity of the third ventricle.

Keywords: BrdU; ependymal cells; hypothalamic development; scRNAseq; tanycytes; third ventricle.

• PMID: 36686420
• PMCID: PMC9849764
• DOI: 10.3389/fendo.2022.1073759

Am J Hum Genet. 2023 Feb 2;110(2):215-227. doi: 10.1016/j.ajhg.2022.12.007. Epub 2022 Dec 30.

Deleterious, protein-altering variants in the transcriptional coregulator ZMYM3 in 27 individuals with a neurodevelopmental delay phenotype

Susan M Hiatt ¹, Slavica Trajkova ², Matteo Rossi Sebastiano ³, E Christopher Partridge ⁴, Fatima E Abidi ⁵, Ashlyn Anderson ⁴, Muhammad Ansar ⁶, Stylianos E Antonarakis ⁷, Azadeh Azadi ⁸, Ruxandra Bachmann-Gagescu ⁹, Andrea Bartuli ¹⁰, Caroline Benech ¹¹, Jennifer L Berkowitz ¹², Michael J Betti ¹³, Alfredo Brusco ², Ashley Cannon ¹⁴, Giulia Caron ³, Yanmin Chen ¹², Meagan E Cochran ⁴, Tanner F Coleman ⁴, Molly M Crenshaw ¹⁵, Laurence Cuisset ¹⁶, Cynthia J Curry ¹⁷, Hossein Darvish ¹⁸, Serwet Demirdas ¹⁹, Maria Descartes ¹⁴, Jessica Douglas ²⁰, David A Dyment ²¹, Houda Zghal Elloumi ¹², Giuseppe Ermondi ³, Marie Faoucher ²², Emily G Farrow ²³, Stephanie A Felker ⁴, Heather Fisher ²⁴, Anna C E Hurst ¹⁴, Pascal Joset ²⁵, Melissa A Kelly ²⁶, Stanislav Kmoch ²⁷, Benjamin R Leadem ¹², Michael J Lyons ⁵, Marina Macchiaiolo ¹⁰, Martin Magner ²⁸, Giorgia Mandrile ²⁹, Francesca Mattioli ³⁰, Megan McEown ⁴, Sarah K Meadows ⁴, Livija Medne ³¹, Naomi J L Meeks ³², Sarah Montgomery ³³, Melanie P Napier ¹², Marvin Natowicz ³⁴, Kimberly M Newberry ⁴, Marcello Niceta ¹⁰, Lenka Noskova ²⁷, Catherine B Nowak ²⁰, Amanda G Noyes ¹², Matthew Osmond ²¹, Eloise J Prijoles ⁵, Jada Pugh ⁴, Verdiana Pullano ², Chloé Quélin ³⁵, Simin Rahimi-Aliabadi ³⁶, Anita Rauch ³⁷, Sylvia Redon ³⁸, Alexandre Reymond ³⁰, Caitlin R Schwager ³⁹, Elizabeth A Sellars ⁴⁰, Angela E Scheuerle ⁴¹, Elena Shukarova-Angelovska ⁴², Cara Skraban ³¹, Elliot Stolerman ⁵, Bonnie R Sullivan ³⁹, Marco Tartaglia ¹⁰, Isabelle Thiffault ²³, Kevin Uguen ³⁸, Luis A Umaña ⁴¹, Yolande van Bever ¹⁹, Saskia N van der Crabben ⁴³, Marjon A van Slegtenhorst ¹⁹, Quinten Waisfisz ⁴⁴, Camerun Washington ⁵, Lance H Rodan ⁴⁵, Richard M Myers ⁴, Gregory M Cooper ⁴⁶Affiliations expand

• PMID: 36586412
• DOI: 10.1016/j.ajhg.2022.12.007

Abstract

Neurodevelopmental disorders (NDDs) result from highly penetrant variation in hundreds of different genes, some of which have not yet been identified. Using the MatchMaker Exchange, we assembled a cohort of 27 individuals with rare, protein-altering variation in the transcriptional coregulator ZMYM3, located on the X chromosome. Most (n = 24) individuals were males, 17 of which have a maternally inherited variant; six individuals (4 male, 2 female) harbor de novo variants. Overlapping features included developmental delay, intellectual disability, behavioral abnormalities, and a specific facial gestalt in a subset of males. Variants in almost all individuals (n = 26) are missense, including six that recurrently affect two residues. Four unrelated probands were identified with inherited variation affecting Arg441, a site at which variation has been previously seen in NDD-affected siblings, and two individuals have de novo variation resulting in p.Arg1294Cys (c.3880C>T). All variants affect evolutionarily conserved sites, and most are predicted to damage protein structure or function. ZMYM3 is relatively intolerant to variation in the general population, is widely expressed across human tissues, and encodes a component of the KDM1A-RCOR1 chromatin-modifying complex. ChIP-seq experiments on one variant, p.Arg1274Trp, indicate dramatically reduced genomic occupancy, supporting a hypomorphic effect. While we are unable to perform statistical evaluations to definitively support a causative role for variation in ZMYM3, the totality of the evidence, including 27 affected individuals, recurrent variation at two codons, overlapping phenotypic features, protein-modeling data, evolutionary constraint, and experimentally confirmed functional effects strongly support ZMYM3 as an NDD-associated gene.

Keywords: X-linked intellectual disability; ZMYM3; chromatin modifiers; neurodevelopmental disorder; transcriptional coregulators.

Life Sci Alliance. 2023 Jan 31;6(4):e202201877. doi: 10.26508/lsa.202201877. Print 2023 Apr.

The ribose methylation enzyme FTSJ1 has a conserved role in neuron morphology and learning performance

Mira Brazane ¹, Dilyana G Dimitrova ¹, Julien Pigeon ², Chiara Paolantoni ³, Tao Ye ⁴, Virginie Marchand ⁵, Bruno Da Silva ¹, Elise Schaefer ⁶, Margarita T Angelova ¹, Zornitza Stark ⁷, Martin Delatycki ⁷, Tracy Dudding-Byth ⁸, Jozef Gecz ⁹, Pierre-Yves Plaçais ¹⁰, Laure Teysset ¹, Thomas Préat ¹⁰, Amélie Piton ⁴, Bassem A Hassan ², Jean-Yves Roignant ^3 11, Yuri Motorin ¹², Clément Carré ¹³

Abstract

FTSJ1 is a conserved human 2′-O-methyltransferase (Nm-MTase) that modifies several tRNAs at position 32 and the wobble position 34 in the anticodon loop. Its loss of function has been linked to X-linked intellectual disability (XLID), and more recently to cancers. However, the molecular mechanisms underlying these pathologies are currently unclear. Here, we report a novel FTSJ1 pathogenic variant from an X-linked intellectual disability patient. Using blood cells derived from this patient and other affected individuals carrying FTSJ1 mutations, we performed an unbiased and comprehensive RiboMethSeq analysis to map the ribose methylation on all human tRNAs and identify novel targets. In addition, we performed a transcriptome analysis in these cells and found that several genes previously associated with intellectual disability and cancers were deregulated. We also found changes in the miRNA population that suggest potential cross-regulation of some miRNAs with these key mRNA targets. Finally, we show that differentiation of FTSJ1-depleted human neural progenitor cells into neurons displays long and thin spine neurites compared with control cells. These defects are also observed in Drosophila and are associated with long-term memory deficits. Altogether, our study adds insight into FTSJ1 pathologies in humans and flies by the identification of novel FTSJ1 targets and the defect in neuron morphology.

• PMID: 36720500
• PMCID: PMC9889914
• DOI: 10.26508/lsa.202201877

Curr Biol. 2023 Jan 9;33(1):164-173.e5. doi: 10.1016/j.cub.2022.11.015. Epub 2022 Dec 6.

Nanog organizes transcription bodies

Ksenia Kuznetsova ¹, Noémie M Chabot ², Martino Ugolini ², Edlyn Wu ², Manan Lalit ³, Haruka Oda ⁴, Yuko Sato ⁴, Hiroshi Kimura ⁴, Florian Jug ⁵, Nadine L Vastenhouw ⁶

Abstract

The localization of transcriptional activity in specialized transcription bodies is a hallmark of gene expression in eukaryotic cells.^1–3 How proteins of the transcriptional machinery come together to form such bodies, however, is unclear. Here, we take advantage of two large, isolated, and long-lived transcription bodies that reproducibly form during early zebrafish embryogenesis to characterize the dynamics of transcription body formation. Once formed, these transcription bodies are enriched for initiating and elongating RNA polymerase II, as well as the transcription factors Nanog and Sox19b. Analyzing the events leading up to transcription, we find that Nanog and Sox19b cluster prior to transcription. The clustering of transcription factors is sequential; Nanog clusters first, and this is required for the clustering of Sox19b and the initiation of transcription. Mutant analysis revealed that both the DNA-binding domain as well as one of the two intrinsically disordered regions of Nanog are required to organize the two bodies of transcriptional activity. Taken together, our data suggest that the clustering of transcription factors dictates the formation of transcription bodies.

Keywords: Nanog; RNA polymerase II; nuclear organization; transcription; transcription bodies; transcription factors; zebrafish.

• PMID: 36476751
• DOI: 10.1016/j.cub.2022.11.015

Sci Adv. 2023 Jan 13;9(2):eade2828. doi: 10.1126/sciadv.ade2828. Epub 2023 Jan 13.

A conditional Smg6 mutant mouse model reveals circadian clock regulation through the nonsense-mediated mRNA decay pathway

Georgia Katsioudi ¹, René Dreos ¹, Enes S Arpa ¹, Sevasti Gaspari ¹, Angelica Liechti ¹, Miho Sato ², Christian H Gabriel ³, Achim Kramer ³, Steven A Brown ², David Gatfield ¹

Abstract

Nonsense-mediated messenger RNA (mRNA) decay (NMD) has been intensively studied as a surveillance pathway that degrades erroneous transcripts arising from mutations or RNA processing errors. While additional roles in physiological control of mRNA stability have emerged, possible functions in mammalian physiology in vivo remain unclear. Here, we created a conditional mouse allele that allows converting the NMD effector nuclease SMG6 from wild-type to nuclease domain-mutant protein. We find that NMD down-regulation affects the function of the circadian clock, a system known to require rapid mRNA turnover. Specifically, we uncover strong lengthening of free-running circadian periods for liver and fibroblast clocks and direct NMD regulation of Cry2 mRNA, encoding a key transcriptional repressor within the rhythm-generating feedback loop. Transcriptome-wide changes in daily mRNA accumulation patterns in the entrained liver, as well as an altered response to food entrainment, expand the known scope of NMD regulation in mammalian gene expression and physiology.

• PMID: 36638184
• DOI: 10.1126/sciadv.ade2828

Alzheimers Res Ther. 2023 Jan 9;15(1):8. doi: 10.1186/s13195-023-01162-4.

Molecular insights into sex-specific metabolic alterations in Alzheimer’s mouse brain using multi-omics approach

Abigail Strefeler ¹, Maxime Jan ², Manfredo Quadroni ³, Tony Teav ¹, Nadia Rosenberg ⁴, Jean-Yves Chatton ⁴, Nicolas Guex ², Hector Gallart-Ayala ⁵, Julijana Ivanisevic ⁶

Free PMC article

Abstract

Background: Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is characterized by altered cellular metabolism in the brain. Several of these alterations have been found to be exacerbated in females, known to be disproportionately affected by AD. We aimed to unravel metabolic alterations in AD at the metabolic pathway level and evaluate whether they are sex-specific through integrative metabolomic, lipidomic, and proteomic analysis of mouse brain tissue.

Methods: We analyzed male and female triple-transgenic mouse whole brain tissue by untargeted mass spectrometry-based methods to obtain a molecular signature consisting of polar metabolite, complex lipid, and protein data. These data were analyzed using multi-omics factor analysis. Pathway-level alterations were identified through joint pathway enrichment analysis or by separately evaluating lipid ontology and known proteins related to lipid metabolism.

Results: Our analysis revealed significant AD-associated and in part sex-specific alterations across the molecular signature. Sex-dependent alterations were identified in GABA synthesis, arginine biosynthesis, and in alanine, aspartate, and glutamate metabolism. AD-associated alterations involving lipids were also found in the fatty acid elongation pathway and lysophospholipid metabolism, with a significant sex-specific effect for the latter.

Conclusions: Through multi-omics analysis, we report AD-associated and sex-specific metabolic alterations in the AD brain involving lysophospholipid and amino acid metabolism. These findings contribute to the characterization of the AD phenotype at the molecular level while considering the effect of sex, an overlooked yet determinant metabolic variable.

Keywords: 3xTg AD mouse; Alzheimer’s disease; Amino acids; Lipidomics; Lysophospholipids; Metabolomics; Multi-omics; Proteomics; Sex differences.

• PMID: 36624525
• PMCID: PMC9827669
• DOI: 10.1186/s13195-023-01162-4