Biology subjects

Medvedeva, V.

Publications and source records attributed to Medvedeva, V..

3 recordsLinked to original sources

bioRxiv2023

Slitrk/LAR-RPTP and disease-associated variants control neuronal migration in the developing mouse cortex independently of synaptic organizer activity

Slitrks and their ligands LAR-RPTPs are type I transmembrane proteins previously implicated in the etiology of various neuropsychiatric disorders including obsessive-compulsive disorders (OCDs) and schizophrenia. Over the last decade, their functions were extensively studied in hippocampal neurons in vitro and shown to shape synapse organization. Although both protein families are highly expressed prior to synapse formation, their function in earlier steps of cerebral cortex development remains unknown. Here we investigated the role of Slitrk1, Slitrk2, Slitrk3 and LAR-RPTPs (Ptprs and Ptprd) in the embryonic mouse cortex by acute genetic manipulation using in utero electroporation. All genes, except Slitrk3, promoted specific alterations in radial migration of glutamatergic neurons. Slitrk1 and Slitrk2 overexpression was associated with accumulation of neurons in distinct regions of the cortical plate. Using deletion mutants and a series of Slitrk variants associated with neurodevelopmental disorders (NDDs), we showed that distinct domains are crucial for intracellular Slitrk1 distribution and/or density and shape of VAMP2+ presynaptic boutons. Interestingly, bouton alterations did not correlate with the observed migration delays, suggesting that Slitrk1 influence cell migration independently on its synaptogenic function. Furthermore, co-electroporation experiments with LAR-RPTPs, mimicking their co-expression observed by scRNAseq, rescued the migration deficits, suggesting possible cis-interactions between Slitrks and LAR-RPTPs. Together, these data indicate that in the embryonic cerebral cortex Slitrks and LAR-RPTPs cooperate in consecutive steps of radial migration through distinct mechanisms than in synapse organization and support a relevant role of Slitrk/LAR-RPTP dysfunctions in NDDs at earlier stages of cortical development.

neuroscience↗

bioRxiv2021

The nuclear ubiquitin ligase adaptor SPOP is a conserved regulator of C9orf72 dipeptide toxicity

A hexanucleotide repeat expansion in the C9orf72 gene is the most common cause of inherited amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Unconventional translation of the C9orf72 repeat produces dipeptide repeat proteins (DPRs). Previously, we showed that the DPRs (PR)50 and (GR)50 are highly toxic when expressed in C. elegans and this toxicity depends on nuclear localization of the DPR. In an unbiased genome-wide RNAi screen for suppressors of (PR)50 toxicity, we identified 12 genes that consistently suppressed either the developmental arrest and/or paralysis phenotype evoked by (PR)50 expression. All of these genes have vertebrate homologs and 7/12 contain predicted nuclear localization signals. One of these genes was spop-1, the C. elegans homolog of SPOP, a nuclear localized E3 ubiquitin ligase adaptor only found in metazoans. SPOP is also required for (GR)50 toxicity and functions in a genetic pathway that includes cul-3, which is the canonical E3 ligase partner for SPOP. Genetic or pharmacological inhibition of SPOP in mammalian primary spinal cord motor neurons suppressed DPR toxicity without affecting DPR expression levels. Finally, we find that genetic inhibition of bet-1, the C. elegans homolog of the known SPOP ubiquitination targets BRD2/3/4, suppresses the protective effect of SPOP mutations. Together, these data suggest a model in which SPOP promotes the DPR-dependent ubiquitination and degradation of BRD proteins. We speculate the pharmacological manipulation of this pathway, which is currently underway for multiple cancer subtypes, could also represent a novel entry point for therapeutic intervention to treat C9 FTD/ALS. Significance statementThe G4C2 repeat expansion in the C9orf72 gene is a major cause of Fronto-Temporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). Unusual translation of the repeat sequence produces two highly toxic dipeptide repeat proteins, PRX and GRX, which accumulate in the brain tissue of individuals with these diseases. Here, we show that PR and GR toxicity in both C. elegans and mammalian neurons depends on the E3 ubiquitin ligase adaptor SPOP. SPOP acts through the bromodomain protein BET-1 to mediate dipeptide toxicity. SPOP inhibitors, which are currently being developed to treat SPOP-dependent renal cancer, also protect neurons against DPR toxicity. Our findings identify a highly conserved and druggable pathway that may represent a new strategy for treating these currently incurable diseases.

neuroscience↗

bioRxiv2019

The PPR14 heterochromatin tether encodes modular domains that mediate and regulate nuclear lamina targeting

A large fraction of epigenetically silent heterochromatin is anchored to the nuclear periphery via \"tethering proteins\" that function to bridge heterochromatin and the nuclear membrane or nuclear lamina. We identified previously a human tethering protein, PRR14, that binds heterochromatin through an N-terminal domain, but the mechanism and regulation of nuclear lamina association remained to be investigated. Here we identify a centrally located, evolutionarily conserved PRR14 nuclear lamina binding domain (LBD) that is both necessary and sufficient for positioning of PRR14 at the nuclear lamina. We also show that PRR14 associates dynamically with the nuclear lamina, and provide evidence that such dynamics are regulated through phosphorylation of the LBD. We also show that the evolutionary conserved PRR14 C-terminal Tantalus domain encodes a PP2A phosphatase recognition site that regulates PRR14 nuclear lamina association. The overall findings demonstrate a heterochromatin anchoring mechanism whereby the PRR14 tether simultaneously binds heterochromatin and the nuclear lamina through two modular domains. Furthermore, the identification of a modular LBD may provide an engineering strategy for delivery of cargo to the nuclear lamina.

cell biology↗