Biology subjects

Tarabykin, V.

Publications and source records attributed to Tarabykin, V..

12 recordsLinked to original sources

bioRxiv2025

A novel role for the CNTN6 locus in lumenization and radial glial cell fate determination during early human cortical development revealed in cerebral organoids

Neurodevelopmental disorders are a class of heterogeneous diseases with a significant genetic contribution, including pathologies resulting from copy number variations (CNVs). Recent advancements in genetic diagnostic technologies have led to the identification of new genes associated with neurodevelopmental disorders through CNVs. One such gene is CNTN6, whose variants and CNVs are associated with intellectual disability and autism spectrum disorders. Cntn6 encodes a neural cell adhesion molecule involved in rodents in axon and dendrite guidance, synapse formation, and oligodendrocyte differentiation, playing a critical role in brain development. However, in humans, the specific molecular and cellular pathogenetic mechanisms remain elusive. Using various techniques to model human brain development pathologies, such as somatic cell reprogramming, cerebral organoids, and genome editing, we established that the CNTN6 locus is involved in the lumenization and cell identity of radial glial cells, as well as in regulating their proliferation. Furthermore, we found that the CNTN6 locus is involved in the nuclear-cytoplasmic translocation of PAX6 protein, a key regulator of forebrain development. Molecular studies revealed that CNTN6 partially functions through the Notch signaling pathway during the early stages of human brain development. Our findings unveil a novel role of the CNTN6 locus in the early stages of human cortical development.

developmental biology↗

bioRxiv2025

Epiproteomic control of the epitranscriptome drives cortical neurogenesis

Neurological conditions are the leading cause of ill health worldwide. Here, we show that the neurodevelopmental disorder-associated ubiquitin ligase UBE3C regulates the cellular composition of the murine cerebral cortex and human brain organoids, with its loss favoring neurogenesis and suppressing glial fate. Using genetic complementation, we demonstrate that disease-associated UBE3C mutations alter its autoubiquitination activity and disrupt cortical lamination. Proteomic profiling of UBE3C-deficient forebrains and organoids identifies Cbll1 as a UBE3C substrate, and we show that the UBE3C-Cbll1 duo drives N6-methyladenosine (m6A) mRNA methylation. Hyperactivation of m6A writers in UBE3C-deficient neural progenitors impairs cell cycle exit, a defect reversible in vivo by the METTL3 inhibitor STM2457. Our findings uncover an epiproteomic mechanism controlling m6A-mediated gene expression and define a regulatory axis linking ubiquitin signaling to epitranscriptomic control of neural fate. This work provides a mechanistic framework for understanding neurodevelopmental disorders and highlights potential therapeutic strategies.

cell biology↗

bioRxiv2025

Neurod2/6 transcription factors control basal progenitor differentiation and sequential production of neocortical cell subtypes

Neurod2 and Neurod6 (Neurod2/6) are key transcription factors that promote neuronal differentiation, however, their role in the developing neocortex is not fully understood. Both genes have similar expression patterns during development as well as binding motifs. In order to investigate their role in cortical neurogenesis, we generated a mouse model deficient for both Neurod2/6. Here we demonstrate that differentiation of Tbr2-positive (Tbr2+) basal progenitors (BPs), but not Pax6+ apical progenitors, was severely defected, resulting in ectopically expanded BPs in perinatal Neurod2/6 deficient brains. The sequential fate specification of cortical neurons was also impaired in the absence of Neurod2/6. Ectopic Tbr2+ BPs expressed multiple proliferation markers and were able to self-renew. Olig2+ glial precursors were consequently over-produced in Neurod2/6 deficient brains. Restoration of Neurod2/6 in the double deficient brains downregulated Tbr2 expression, and exhibited substantial rescue effects on defected laminar subtype specification and excessive gliogenesis. Our work indicates that Neurod2/6 regulate BP differentiation and sequential production of cortical cell subtypes via inhibiting Tbr2-dependent genetic program.

neuroscience↗

bioRxiv2025

Nurr1 orchestrates claustrum development and functionality

Claustrum is the part of the forebrain known to be most widely interconnected tissue with almost all global regions. It is believed to be involved in coordinating multiple cognitive behaviors including consciousness formation. However, little is known about the molecular mechanisms underlying its development and involvement in behavioral control. Here we show that Nurr1 (Nr4a2) is the key transcription factor orchestrating claustral morphogenesis, functional connectivity and thus behaviors. Nurr1 deficient claustral cells aberrantly migrate into insular cortex, shaping claustrum into an abnormal wing-like structure, and ectopically turn on insular corticex genetic program. Accordingly, functional connectivity of the claustrum is not properly formed and relevant behaviors are dysregulated in Nurr1 deficient mice. We show that Nurr1 regulates claustral neuron positioning by suppressing G-protein signaling.

neuroscience↗

bioRxiv2023

Sema7A and Sema4D Heterodimerization is Essential for Membrane Targeting and Neocortical Wiring

Disruption of neocortical circuitry and architecture in humans causes numerous neurodevelopmental disorders. Neocortical cytoarchitecture is orchestrated by various transcription factors such as Satb2 that control target genes during strict time windows. In humans, mutations of SATB2 cause SATB2 Associated Syndrome (SAS), a multisymptomatic syndrome involving intellectual disability, speech delay, epilepsy and craniofacial defects. We show that Satb2 controls neuronal migration and axonal outgrowth by inducing the expression of the GPI-anchored protein, Sema7A. We find that heterodimerization with Sema4D increases targeting of Sema4D to the membrane and is required for Sema7A function. Finally, we report that membrane localization and pos- translational modification of the Sema7A-Sema4D complex is disrupted by a novel de novo mutation in Sema4D (Q497P) that is associated with epilepsy in humans. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=197 HEIGHT=200 SRC="FIGDIR/small/527998v1_ufig1.gif" ALT="Figure 1"> View larger version (48K): org.highwire.dtl.DTLVardef@db698org.highwire.dtl.DTLVardef@4ee980org.highwire.dtl.DTLVardef@c3d9d6org.highwire.dtl.DTLVardef@12a135_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISema7A is a direct Satb2 target that drives neuronal migration and axon outgrowth C_LIO_LISema7A exerts its effect by heterodimerizing with Sema4D at neurites and growth cones C_LIO_LISema7A increases cell surface localization of Sema4D C_LIO_LIDe novo human Sema4D-Q497P mutation causes epilepsy, inhibits post-translational processing & surface localization C_LI eTOCSema7A is a direct target of the transcription factor Satb2. Sema7A promotes normal migration and axon outgrowth in cortical neurons by modulating reverse signaling via Sema4D. These processes are dependent on Sema7A-Sema4D heterodimerization and membrane localization; insufficient transcription of Sema7A or incomplete glycosylation of Sema4D inhibit this progression.

neuroscience↗

bioRxiv2022

HP1 deficiency results in De-Repression of Endogenous Retroviruses and Induction of Neurodegeneration via Complement

In aging cells and animal models of premature aging, heterochromatin loss coincides with transcriptional disruption including the activation of normally silenced endogenous retroviruses (ERVs). Here we show that loss of heterochromatin maintenance and de-repression of ERVs results in a chronic inflammatory environment characterized by neurodegeneration and cognitive decline. We discovered differential contributions of HP1 proteins to ERV silencing where HP1{gamma} is necessary and sufficient for H4K20me3 deposition and HP1{beta} deficiency causes aberrant DNA methylation. Combined loss of HP1{beta} and HP1{gamma} resulted in loss of DNA methylation at ERVK elements. Progressive ERV de-repression in HP1{beta}/{gamma} DKO mice was followed by stimulation of the integrated stress response, an increase of Complement 3+ reactive astrocytes and phagocytic microglia. This chronic inflammatory state coincided with age-dependent reductions in dendrite complexity and cognition. Our results demonstrate the importance of preventing loss of epigenetic maintenance, as this will be the only way postmitotic neuronal genomes can be protected and/or renewed. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/505641v4_ufig1.gif" ALT="Figure 1"> View larger version (65K): org.highwire.dtl.DTLVardef@f5feb7org.highwire.dtl.DTLVardef@25d73dorg.highwire.dtl.DTLVardef@5604a4org.highwire.dtl.DTLVardef@14ad84a_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Timed global reorganization of protein synthesis during neocortex neurogenesis at codon resolution

Translation modulates the timing and amplification of gene expression after transcription. Brain development requires uniquely complex gene expression patterns, but large-scale measurements of translation directly in the prenatal brain are lacking. We measure the reactants, synthesis, and products of translation spanning mouse neocortex neurogenesis, and discover a transient window of dynamic regulation at mid-gestation. Timed translation upregulation of chromatin binding proteins like Satb2, which is essential for neuronal subtype differentiation, restricts protein expression in neuronal lineages despite broad transcriptional priming in progenitors. In contrast, translation downregulation of ribosomal proteins sharply decreases ribosome number, coinciding with a major shift in protein synthesis dynamics at mid-gestation. Changing levels of eIF4EBP1, a direct inhibitor of ribosomal protein translation, are concurrent with ribosome downregulation and controls Satb2 fate acquisition during neuronal differentiation. Thus, the refinement of transcriptional programs by translation is central to the molecular logic of brain development. Modeling of the developmental neocortex translatome is provided as an open-source searchable resource: https://shiny.mdc-berlin.de/cortexomics/.

neuroscience↗

bioRxiv2021

Ire1α-Regulated Rate of mRNA Translation is Required for Acquisition of Identity and Polarity in Upper Layer Cortical Neurons

Evolutionary expansion of the neocortex is associated with the increase in upper layer neurons. Here, we present Inositol-Requiring Enzyme 1, Ire1, as an essential determinant of upper layer fate, neuronal polarization and cortical lamination. We demonstrate a non-canonical function of Ire1 in the regulation of global translation rates in the developing neocortex through its dynamic interaction with the ribosome and regulation of eIF4A1 and eEF-2 expression. Inactivation of Ire1 engenders lower protein synthesis rates associated with stalled ribosomes and decreased number of translation start sites. We show unique sensitivity of upper layer fate to translation rates. Whereas eEF-2 is required for cortical lamination, eIF4A1 regulates acquisition of upper layer fate downstream of Ire1 in a mechanism of translational control dependent on 5UTR-embedded structural elements in fate determinant genes. Our data unveil developmental regulation of ribosome dynamics as post-transcriptional mechanisms orchestrating neuronal diversity establishment and assembly of cortical layers. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=93 SRC="FIGDIR/small/449563v2_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@115a09aorg.highwire.dtl.DTLVardef@e30d2dorg.highwire.dtl.DTLVardef@763b27org.highwire.dtl.DTLVardef@2586e9_HPS_FORMAT_FIGEXP M_FIG C_FIG HIGHLIGHTSO_LISmall molecule screening reveals Ire1 upstream of upper layer neuronal identity C_LIO_LIPolarization and proper lamination of layer II/III neurons require Ire1 C_LIO_LIDevelopment of upper layers requires high translation rates driven by eIF4A1 and eEF-2 downstream of Ire1 C_LIO_LIeIF4A1-dependent Satb2 mRNA translation initiation is a mechanism of upper layer fate acquisition C_LI

neuroscience↗

bioRxiv2020

Olig3 acts as a master regulator of cerebellar development

The mature cerebellum controls motor skill precision and participates in other sophisticated brain functions that include learning, cognition and speech. Different types of GABAergic and glutamatergic cerebellar neurons originate in temporal order from two progenitor niches, the ventricular zone and rhombic lip, which express the transcription factors Ptf1a and Atoh1, respectively. However, the molecular machinery required to specify the distinct neuronal types emanating from these progenitor zones is still unclear. Here, we uncover the transcription factor Olig3 as a major determinant in generating the earliest neuronal derivatives emanating from both progenitor zones. In the rhombic lip, Olig3 regulates progenitor cell proliferation. In the ventricular zone, Olig3 safeguards Purkinje cell specification by curtailing the expression of Pax2, a transcription factor that we found to impose an inhibitory interneuron identity. Our work thus defines Olig3 as a key factor in cerebellar development.

neuroscience↗

bioRxiv2020

The architecture of protein synthesis in the developing neocortex at near-atomic resolution reveals Ebp1-mediated neuronal proteostasis at the 60S tunnel exit

Protein synthesis must be finely tuned in the nervous system, as it represents an essential feature of neurodevelopmental gene expression, and dominant pathology in neurological disease. However, the architecture of ribosomal complexes in the developing mammalian brain has not been analyzed at high resolution. This study investigates the architecture of ribosomes ex vivo from the embryonic and perinatal mouse neocortex, revealing Ebp1 as a 60S peptide tunnel exit binding factor at near-atomic resolution by multiparticle cryo-electron microscopy. The impact of Ebp1 on the neuronal proteome was analyzed by pSILAC and BONCAT coupled mass spectrometry, implicating Ebp1 in neurite outgrowth proteostasis, with in vivo embryonic Ebp1 knockdown resulting in dysregulation of neurite outgrowth. Our findings reveal Ebp1 as a central component of neocortical protein synthesis, and the 60S peptide tunnel exit as a focal point of gene expression control in the molecular specification of neuronal morphology. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=200 SRC="FIGDIR/small/939488v1_ufig1.gif" ALT="Figure 1"> View larger version (59K): org.highwire.dtl.DTLVardef@1231351org.highwire.dtl.DTLVardef@1c940f7org.highwire.dtl.DTLVardef@1c81e2corg.highwire.dtl.DTLVardef@135008b_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2019

Human endogenous retrovirus HERV-K(HML-2) RNA causes neurodegeneration through Toll-like receptors

Although human endogenous retroviruses (HERVs) represent a substantial proportion of the human genome and some HERVs have been suggested to be involved in neurological disorders, little is known about their biological function and pathophysiological relevance. HERV-K(HML-2) comprises evolutionarily young proviruses transcribed in the brain. We report that RNA derived from an HERV-K(HML-2) env gene region binds to the human RNA-sensing Toll-like receptor (TLR) 8, activates human TLR8, as well as murine Tlr7, and causes neurodegeneration through TLR8 and Tlr7 in neurons and microglia. HERV-K(HML-2) RNA introduced extracellularly into the cerebrospinal fluid (CSF) of either C57BL/6 wild-type mice or APPPS1 mice, a mouse model for Alzheimers disease (AD), resulted in neurodegeneration. Tlr7-deficient mice were protected against neurodegenerative effects, but were re-sensitized towards HERV-K(HML-2) RNA when neurons ectopically expressed murine Tlr7 or human TLR8. Accordingly, transcriptome datasets of human brain samples from AD patients revealed a specific correlation of upregulated HERV-K(HML-2) and TLR8 RNA expression. HERV-K(HML-2) RNA was detectable more frequently in CSF from AD individuals compared to controls. Our data establish HERV-K(HML-2) RNA as an endogenous ligand for human TLR8 and murine Tlr7 and imply a functional contribution of specific human endogenous retroviral transcripts to neurodegenerative processes such as AD.

neuroscience↗

bioRxiv2019

The Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc.

Kaufman oculocerebrofacial syndrome (KOS) is a severe autosomal recessive disorder characterized by intellectual disability, developmental delays, microcephaly and characteristic dysmorphisms. Biallelic mutations of UBE3B, encoding for a ubiquitin ligase E3B are causative for KOS. In this report, we characterize neuronal functions of its murine ortholog Ube3b. We show that Ube3b regulates dendritic branching in a cell-autonomous manner. Moreover, Ube3b knockout (KO) neurons exhibit increased density and aberrant morphology of dendritic spines, altered synaptic physiology and changes in hippocampal circuit activity. Dorsal forebrain-specific Ube3b KO animals show impaired spatial learning and alterations in social interactions. We further demonstrate that Ube3b ubiquitinates the catalytic {gamma}-subunit of calcineurin (Ppp3cc), the overexpression of which phenocopies the loss of Ube3b with regard to dendritic spine density. This work provides insights into the molecular pathologies underlying intellectual disability-like phenotypes in a genetic mouse model for KOS.

neuroscience↗