CELF4 regulates spine formation and depression-like behaviors of mice

Shen, Ying; Zhang, Cuiping; Xiao, Kaimin; Liu, Dixiu; Guang-ping, Xie

doi:10.1016/j.bbrc.2022.03.067

Cited by 4 publications

(3 citation statements)

References 39 publications

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“…3g ) and RIP-RNA seq data (Figs. 2 f, 3c ) suggest that early prenatal Celf4 loss from excitatory neurons may result in various synaptic defects in the SP, potentially impairing cortical excitability postnatally and causing epilepsy and depression 79 , 80 , 92 . Moreover, the identified sex-specific roles of Celf4 in mice suggest that the translational control may be the point of sex-dependent vulnerability in the number of NDDs, including the ASD.…”

Section: Discussionmentioning

confidence: 99%

Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex

Salamon,

Park,

Miškić

et al. 2023

Nat Commun

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Abnormalities in neocortical and synaptic development are linked to neurodevelopmental disorders. However, the molecular and cellular mechanisms governing initial synapse formation in the prenatal neocortex remain poorly understood. Using polysome profiling coupled with snRNAseq on human cortical samples at various fetal phases, we identify human mRNAs, including those encoding synaptic proteins, with finely controlled translation in distinct cell populations of developing frontal neocortices. Examination of murine and human neocortex reveals that the RNA binding protein and translational regulator, CELF4, is expressed in compartments enriched in initial synaptogenesis: the marginal zone and the subplate. We also find that Celf4/CELF4-target mRNAs are encoded by risk genes for adverse neurodevelopmental outcomes translating into synaptic proteins. Surprisingly, deleting Celf4 in the forebrain disrupts the balance of subplate synapses in a sex-specific fashion. This highlights the significance of RNA binding proteins and mRNA translation in evolutionarily advanced synaptic development, potentially contributing to sex differences.

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Section: Discussionmentioning

confidence: 99%

Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex

Salamon,

Park,

Miškić

et al. 2023

Nat Commun

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“…In particular, some genes with a large fold-change in expression after exposure to GCs and a high correlation with the inhibitory neuron lineage were direct or second-order targets of PBX3 in the GRN of organoids exposed to GC. Examples included CELF4, a gene associated with synaptic development 43 , depression-like behavior in mice 44 , and ASD 45 . Another example was SYNPR, a common inhibitory neuron marker gene 46,47 (Fig.…”

Section: Resultsmentioning

confidence: 99%

Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids

Dony,

Krontira,

Kaspar

et al. 2024

Preprint

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Disruptions in the tightly regulated process of human brain development have been linked to increased risk for brain and mental illnesses. While the genetic contribution to these diseases is well established, important environmental factors have been less studied at molecular and cellular levels. In this study, we used single-cell and cell-type-specific techniques to investigate the effect of glucocorticoid (GC) exposure, a mediator of antenatal environmental risk, on gene regulation and lineage specification in unguided human neural organoids. We characterized the transcriptional response to chronic GC exposure during neural differentiation and studied the underlying gene regulatory networks by integrating single-cell transcriptomics- with chromatin accessibility data. We found lasting cell type-specific changes that included autism risk genes and several transcription factors associated with neurodevelopment. Chronic GCs influenced lineage specification primarily by priming the inhibitory neuron lineage through key transcription factors like PBX3. We provide evidence for convergence of genetic and environmental risk factors through a common mechanism of altering lineage specification.

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“…Finally, CUGBP Elav-Like Family Member 4 ( CELF4 ) is a neuronal RNA-binding protein that targets genes associated with the regulation of neuronal excitation, synaptic plasticity, and transmission [ 23 ]. CELF4 levels were recently shown to be decreased in an animal model of depression along with decreased spine number [ 24 ].…”

Section: Molecular Pathways and Systemsmentioning

confidence: 99%

Molecular pathways of major depressive disorder converge on the synapse

et al. 2022

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Major depressive disorder (MDD) is a psychiatric disease of still poorly understood molecular etiology. Extensive studies at different molecular levels point to a high complexity of numerous interrelated pathways as the underpinnings of depression. Major systems under consideration include monoamines, stress, neurotrophins and neurogenesis, excitatory and inhibitory neurotransmission, mitochondrial dysfunction, (epi)genetics, inflammation, the opioid system, myelination, and the gut-brain axis, among others. This review aims at illustrating how these multiple signaling pathways and systems may interact to provide a more comprehensive view of MDD’s neurobiology. In particular, considering the pattern of synaptic activity as the closest physical representation of mood, emotion, and conscience we can conceptualize, each pathway or molecular system will be scrutinized for links to synaptic neurotransmission. Models of the neurobiology of MDD will be discussed as well as future actions to improve the understanding of the disease and treatment options.

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CELF4 regulates spine formation and depression-like behaviors of mice

Cited by 4 publications

References 39 publications

Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex

Celf4 controls mRNA translation underlying synaptic development in the prenatal mammalian neocortex

Chronic exposure to glucocorticoids amplifies inhibitory neuron cell fate during human neurodevelopment in organoids

Molecular pathways of major depressive disorder converge on the synapse

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