Role of Y-Box Binding Proteins in Ontogenesis

Kretov, Dmitry A.

doi:10.1134/s0006297922140061

Cited by 2 publications

(1 citation statement)

References 180 publications

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“…To strengthen the translatability of our findings by focusing on conserved functions, we decided to study the C. elegans ortholog(s) that are the most closely related to the YBX proteins (53,54,57,65,66). To this end, we performed phylogeny and homology analysis using MegaX and DIOPT (67,68) and found that cey-1 is the primary C. elegans YBX ortholog, closer in similarity to the YBXs than other CEY family members ( Figure 2A, 2B ).…”

Section: Resultsmentioning

confidence: 99%

Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition

Hayden,

Brandel,

Merlau

et al. 2024

Preprint

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RNA-binding proteins (RBPs) are key regulators of translation and plasticity in the nervous system, which are processes required for learning and memory. Indeed, RBP dysfunction has been linked to a wide range of neurological disorders where cognitive impairments are a key symptom. However, the human genome encodes nearly 2,000 RBPs, many of which have yet to be characterized with regards to neurological phenotypes like associative behaviors. To address this, we used the model organismC. elegansto perform a targeted screen assessing the role of 20 conserved RBPs in learning and memory. We identified 16 associative memory regulators, eight of which are novel. Intriguingly, three novel memory regulators are in theC. elegansY-Box (CEY) RNA-binding protein family:cey-1, cey-2, andcey-3. We determined thatcey-1is the closest ortholog to the mammalian Y-Box RNA-binding (YBX) proteins and that CEY-1 is specifically required in the nervous system for the ability to remember. Additionally, CEY-1 is a memory promoting molecule, as increasing CEY-1 only in the nervous system improves memory. We also examined human copy number variation datasets and found that copy number deletions in the humanYBX1andYBX3may be associated with neurological symptoms including intellectual disability, which mirror our findings inC. elegans. We identified a similar association with a rare, mono-allelicYBX3variant in individuals with neurological findings. Strikingly, introducing this predicted deleteriousYBX3variant into the endogenouscey-1locus caused memory deficits in the worm. Our study highlights that high-throughput approaches in the worm reveal novel and conserved regulators of memory and identified a potential new source of rare neurological disease linked to RBP dysfunction.

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Section: Resultsmentioning

confidence: 99%

Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition

Hayden,

Brandel,

Merlau

et al. 2024

Preprint

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Behavioral screening reveals a conserved residue in Y-Box RNA-binding protein required for associative learning and memory in C. elegans

Hayden,

Brandel,

Pietryk

et al. 2024

PLoS Genet

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RNA-binding proteins (RBPs) regulate translation and plasticity which are required for memory. RBP dysfunction has been linked to a range of neurological disorders where cognitive impairments are a key symptom. However, of the 2,000 RBPs in the human genome, many are uncharacterized with regards to neurological phenotypes. To address this, we used the model organism C. elegans to assess the role of 20 conserved RBPs in memory. We identified eight previously uncharacterized memory regulators, three of which are in the C. elegans Y-Box (CEY) RBP family. Of these, we determined that cey-1 is the closest ortholog to the mammalian Y-Box (YBX) RBPs. We found that CEY-1 is both necessary in the nervous system for memory ability and sufficient to promote memory. Leveraging human datasets, we found both copy number variation losses and single nucleotide variants in YBX1 and YBX3 in individuals with neurological symptoms. We identified one predicted deleterious YBX3 variant of unknown significance, p.Asn127Tyr, in two individuals with neurological symptoms. Introducing this variant into endogenous cey-1 locus caused memory deficits in the worm. We further generated two humanized worm lines expressing human YBX3 or YBX1 at the cey-1 locus to test evolutionary conservation of YBXs in memory and the potential functional significance of the p.Asn127Tyr variant. Both YBX1/3 can functionally replace cey-1, and introduction of p.Asn127Tyr into the humanized YBX3 locus caused memory deficits. Our study highlights the worm as a model to reveal memory regulators and identifies YBX dysfunction as a potential new source of rare neurological disease.

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Role of Y-Box Binding Proteins in Ontogenesis

Cited by 2 publications

References 180 publications

Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition

Behavioral screening of conserved RNA-binding proteins reveals CEY-1/YBX RNA-binding protein dysfunction leads to impairments in memory and cognition

Behavioral screening reveals a conserved residue in Y-Box RNA-binding protein required for associative learning and memory in C. elegans

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