Distinct cis elements in the 3′ UTR of the C. elegans cebp-1 mRNA mediate its regulation in neuronal development

Sharifnia, Panid; Kim, Kyung Won; Wu, Zilu; Jin, Yishi

doi:10.1016/j.ydbio.2017.06.022

Cited by 4 publications

(3 citation statements)

References 33 publications

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“…While cebp-1(ju1590) [#9: ΔQ62] reduced PLM axon regrowth to similar degree as cebp-1(ju634) [#3: R63P], cebp-1(ju1521) [#5: D64N] showed partially reduced axon regrowth, comparing to cebp-1(ju634) (Figure 1B). This finding is consistent with previous findings that axon regeneration is highly sensitive to CEBP-1 activity levels (Sharifnia et al, 2017), and CEBP-1(D64N) mutation causes partial loss of function. Together, these results strongly support that this stretch of 15 amino acids within the N-terminus of CEBP-1 defines a functional domain, named as N’ domain.…”

Section: Resultssupporting

confidence: 93%

Functional Dissection of C. elegans bZip-Protein CEBP-1 Reveals Novel Structural Motifs Required for Axon Regeneration and Nuclear Import

Malinow

Ying

Koorman

et al. 2019

Front. Cell. Neurosci.

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The basic leucine-zipper (bZIP) domain transcription factors CCAAT/enhancer-binding proteins (C/EBP) have a variety of roles in cell proliferation, differentiation, and stress response. In the nervous system, several isoforms of C/EBP function in learning and memory, neuronal plasticity, neuroinflammation, and axon regeneration. We previously reported that the Caenorhabditis elegans C/EBP homolog, CEBP-1, is essential for axon regeneration. CEBP-1 consists of 319 amino acids, with its bZIP domain at the C-terminus and a long N-terminal fragment with no known protein motifs. Here, using forward genetic screening with targeted genome editing, we have identified a unique domain in the N-terminus that is critical for its in vivo function. Additionally, we characterized three nuclear localization signals (NLS) in CEBP-1 that act together to mediate CEBP-1’s nuclear import. Moreover, the Importin-α, IMA-3, can bind to CEBP-1 via one of the NLS. ima-3 is ubiquitously expressed in all somatic cells, and ima-3 null mutants are larval lethal. Using Cre-lox dependent neuron-specific deletion strategy, we show that ima-3 is not critical for axon development, but is required for axon regeneration in adults. Together, these data advance our understanding of CEBP-1’s function, and suggest new regulators that remain to be identified to expand the CEBP-1 protein interactome.

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Section: Resultssupporting

confidence: 93%

Functional Dissection of C. elegans bZip-Protein CEBP-1 Reveals Novel Structural Motifs Required for Axon Regeneration and Nuclear Import

Malinow

Ying

Koorman

et al. 2019

Front. Cell. Neurosci.

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“…What is unclear is whether those discrete locations represent synapses in touch axons. In addition, a putative stem-loop secondary structure was identified in the cebp-1 3’UTR that inhibits cebp-1 mRNA stability or its translation( 39 ). Thus, the cebp-1 3’UTR appears to have both positive and negative impacts on cebp-1 gene expression.…”

Section: Resultsmentioning

confidence: 99%

Thekpc-13’UTR facilitates dendritic transport and translation of mRNAs for dendrite arborization of a mechanosensory neuron important for male courtship

Zou

Shih

Chiu

et al. 2021

Preprint

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Mechanical stimuli on the skin of C. elegans are detected by the dendritic arbors of PVD nociceptive neurons, which provide uniform sensory coverage outside the head region across the entire animal. Through genetic screens, we isolate three mutants that display profound dendrite self-avoidance defects in PVD neurons. Studying dendrite self-avoidance in C. elegans is likely to provide new mechanistic insight into the process as the well-known self-avoidance molecule Dscam is absent from the C. elegans genome. Through whole genome sequencing, we identify the responsible mutations in the kpc-1 gene. Compared to wild-type animals, a strong kpc-1 mutant allele exhibits secondary dendrite branching defects whereas a weak kpc-1 mutant allele displays tertiary dendrite self-avoidance defects. Here, we show that the kpc-1 3′UTR is required for kpc-1′s functions in both dendrite branching and dendrite self-avoidance. The kpc-1 3′UTR facilitates kpc-1 RNA localization to branching points and contact points between sibling dendrites. Using fluorescence recovery after photoconversion, we show that the kpc-1 3′UTR promotes local protein synthesis in the distal segment of PVD dendrites. We identify an important secondary structural motif in the kpc-1 3′UTR required for tertiary dendrite self-avoidance. We demonstrate that over-expression of kpc-1 leads to greater self-avoidance without limiting initial dendrite outgrowth, supporting a direct role of kpc-1 in self-avoidance. Animals with dma-1 receptor over-expression display similar secondary dendrite branching and tertiary dendrite self-avoidance defects that are suppressed with kpc-1 over-expression, which suggests that DMA-1 is a potential KPC-1 target that is down-regulated by KPC-1. Our results support a model where KPC-1 proteins are synthesized at branching points and contact points between neighboring dendrites to locally down-regulate DMA-1 receptors to promote dendrite branching and self-avoidance. A recently reported Schizophrenia-associated genetic variant in the 3′UTR of the human furin gene, a homolog of kpc-1, highlights the important role of the kpc-1(furin) 3′UTR in neuronal development, which is further demonstrated by this mechanistic study.

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“…此外, Riveiro等人 [41] 利用CRISPR技术揭示了组氨酸去甲基化酶JMJD-1.2调控秀丽线虫轴突导向 (axon guidance)的机制. 同样在2017年, Sharifnia等人 [42] 通过CRISPR技术研究了cebp-1基因顺式调控元件在秀丽线虫神经发育中的作用. 最近, 中国科学院神经科学研究所的蔡时青研究组 [43] [48] 结合 FLP和CRISPR技术实现了线虫特定组织baf-1基因的敲除.…”

Section: Crispr/cas9技术在秀丽线虫中的应用unclassified

Application advances and prospects of CRISPR/Cas9 genome editing in nematodes

Cao¹,

Zhang²

2018

Sci. Sin.-Vitae

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Distinct cis elements in the 3′ UTR of the C. elegans cebp-1 mRNA mediate its regulation in neuronal development

Cited by 4 publications

References 33 publications

Functional Dissection of C. elegans bZip-Protein CEBP-1 Reveals Novel Structural Motifs Required for Axon Regeneration and Nuclear Import

Functional Dissection of C. elegans bZip-Protein CEBP-1 Reveals Novel Structural Motifs Required for Axon Regeneration and Nuclear Import

Thekpc-13’UTR facilitates dendritic transport and translation of mRNAs for dendrite arborization of a mechanosensory neuron important for male courtship

Application advances and prospects of CRISPR/Cas9 genome editing in nematodes

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