The RNA-binding protein Celf6 is highly expressed in diencephalic nuclei and neuromodulatory cell populations of the mouse brain

Maloney, Susan E.; Khangura, Eakta; Dougherty, Joseph D.

doi:10.1007/s00429-015-1005-z

Cited by 11 publications

(16 citation statements)

References 31 publications

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“…1 Behavioral impairments were observed in two tasks. 4 Specifically, robust expression of the protein was observed in the neuromodulatory transmitter-expressing nuclei, including noradrenergic and dopaminergic populations, and, as expected, 5-HT cells. Second, as adults, Celf6 −/− mice displayed a different response pattern compared to littermate controls in the holeboard task, a measure used to assess exploration and olfactory preference, and how they may be related to perseverative behavior.…”

supporting

confidence: 65%

“…1 Subsequent deep characterization of the temporal and spatial expression patterns of CELF6 RNA and protein in the brain showed these gene products are present early in a subset of neurons during neurodevelopment and into adulthood, peaking around birth. 4 Specifically, robust expression of the protein was observed in the neuromodulatory transmitter-expressing nuclei, including noradrenergic and dopaminergic populations, and, as expected, 5-HT cells. There was also robust expression in the hypothalamus, cholinergic cells of the striatum and other aspects of the limbic system.…”

supporting

confidence: 65%

“…46,47 Celf6 is highly expressed in the monoamine-expressing cell populations, specifically the locus coeruleus (noradrenergic), raphe nuclei (serotonergic) and the ventral tegmental area and substantia nigra (dopaminergic; Ref. 4). In addition, levels of these neurotransmitters are reduced in brains that lack Celf6.…”

Section: Discussionmentioning

confidence: 99%

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Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning

Maloney

Rieger

Al‐Hasani

et al. 2019

Genes Brain and Behavior

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In addition to gene expression differences in distinct cell types, there is substantial post‐transcriptional regulation driven in part by RNA binding proteins (RBPs). Loss‐of‐function RBP mutations have been associated with neurodevelopmental disorders, such as Fragile‐X syndrome and syndromic autism. Work performed in animal models to elucidate the influence of neurodevelopmental disorder‐associated RBPs on distinct behaviors has showed a connection between normal post‐transcriptional regulation and conditioned learning. We previously reported cognitive inflexibility in a mouse model null for the RBP CUG‐BP, Elav‐like factor 6 (CELF6), which we also found to be associated with human autism. Specifically, these mice failed to potentiate exploratory hole‐poking behavior in response to familiarization to a rewarding stimuli. Characterization of Celf6 gene expression showed high levels in monoaminergic populations such as the dopaminergic midbrain populations. To better understand the underlying behavioral disruption mediating the resistance to change exploratory behavior in the holeboard task, we tested three hypotheses: Does Celf6 loss lead to global restricted patterns of behavior, failure of immediate response to reward or failure to alter behavior in response to reward (conditioning). We found the acute response to reward was intact, yet Celf6 mutant mice exhibited impaired conditioned learning to both reward and aversive stimuli. Thus, we found that the resistance to change by the Celf6 mutant in the holeboard was most parsimoniously explained as a failure of conditioning, as the mice had blunted responses even to potent rewarding stimuli such as cocaine. These findings further support the role of RBPs in conditioned learning.

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supporting

confidence: 65%

supporting

confidence: 65%

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Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning

Maloney

Rieger

Al‐Hasani

et al. 2019

Genes Brain and Behavior

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“…To define the in vivo binding locations of CELF6, we performed CLIP on brains from BAC transgenic mice expressing an epitope tagged CELF6-YFP/HA (78 kDa) with the endogenous CELF6 pattern (9). As CELF6 molecular function has not been studied in vivo, we first confirmed CELF6 binds RNA in the brain.…”

Section: Celf6 Primarily Associates With 3'utrs Of Target Mrnas In Vivomentioning

confidence: 98%

“…Our laboratory identified CELF6 as both enriched in serotonin producing neurons and disrupted in an individual with autism (8). Upon further study, CELF6 also showed enriched expression in the hypothalamus and in several monoaminergic cell populations commonly targeted for treatment in psychiatry (9). Functionally, CELF6 has been shown capable of regulating splicing in vitro (10), however its targets and function in vivo are uncharacterized.…”

Section: Introductionmentioning

confidence: 96%

CLIP-Seq and massively parallel functional analysis of the CELF6 RNA binding protein reveals a role in destabilizing synaptic gene mRNAs through interaction with 3’UTR elements in vivo

Rieger

King

Cohen

et al. 2018

Preprint

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CELF6 is an RNA-binding protein in a family of proteins with roles in human health and disease, however little is known about the mRNA targets or in vivo function of this protein.We utilized HITS-CLIP/CLIP-Seq to identify, for the first time, in vivo targets of CELF6 and identify hundreds of transcripts bound by CELF6 in the brain. We found these are disproportionately mRNAs coding for synaptic proteins. We then conducted extensive functional validation of these targets, testing greater than 400 CELF6 bound sequence elements for their activity, applying a massively parallel reporter assay framework to evaluation of the CLIP data. We also mutated every potential CELF6 binding motif within these elements and tested their impact. This comprehensive analysis led us to ascribe a previously unknown function to CELF6: we found bound elements were generally repressive of translation, that CELF6 further enhances this repression via decreasing RNA abundance, and this process was dependent on UGU-rich sequence motifs. This greatly extends the known role for CELF6, which had previously been defined only as a splicing factor. We further extend these findings by demonstrating the same function for CELF3, CELF4, and CELF5. Finally, we demonstrate that the CELF6 targets are derepressed in CELF6 mutant mice in vivo, confirming this new role in the brain. Thus, our study demonstrates that CELF6 and other sub-family members are repressive CNS RNA-binding proteins, and CELF6 downregulates specific mRNAs in vivo.

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CELF6 modulates triple-negative breast cancer progression by regulating the stability of FBP1 mRNA

Yang

Zhao

Pei

et al. 2020

Breast Cancer Res Treat

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The RNA-binding protein Celf6 is highly expressed in diencephalic nuclei and neuromodulatory cell populations of the mouse brain

Cited by 11 publications

References 31 publications

Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning

Loss of CELF6 RNA binding protein impairs cocaine conditioned place preference and contextual fear conditioning

CLIP-Seq and massively parallel functional analysis of the CELF6 RNA binding protein reveals a role in destabilizing synaptic gene mRNAs through interaction with 3’UTR elements in vivo

CELF6 modulates triple-negative breast cancer progression by regulating the stability of FBP1 mRNA

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