Cell-type-specific and developmental regulation of heterogeneous nuclear ribonucleoprotein K mRNA in the rat nervous system

Blanchette, Adam R.; Medel, Yuly F. Fuentes; Gardner, Paul

doi:10.1016/j.modgep.2005.11.008

Cited by 14 publications

(13 citation statements)

References 39 publications

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“…The expression and distribution pattern of most hnRNPs in neural tissues especially in the retina is largely unknown except the hnRNP-K [21]. In the present study, we demonstrate that in the adult rat retina, hnRNP-R1 is expressed in the OPL, INL and GCL and mainly distributed in bipolar cells, amacrine cells and ganglion cells.…”

Section: Discussionsupporting

confidence: 51%

The Expression Pattern of Heterogeneous Nuclear Ribonucleoprotein R in Rat Retina

et al. 2008

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The heterogeneous nuclear ribonucleoproteins (hnRNPs) play important roles in DNA repairing, cell signaling, telomere biogenesis, and in regulating gene expression at both transcriptional and translational levels. In the present study, we demonstrated that the expression of hnRNP-R1 and hnRNP-R2 is developmentally regulated in rat retina. The neural specific isoform hnRNP-R2 is expressed in 7-day postnatal rat retina, but not in the adult retina. The positive immunohistochemistry signal of hnRNP-R1 is extensively distributed in the outer plexiform layer, inner nuclear layer and ganglion cell layer of rat retina. Double staining experiments showed that the positive signal of hnRNP-R1 is distributed in ON-type bipolar cells and localized in the cytoplasm, dendrites and axon terminals. In addition, the hnRNP-R1 distribution is regulated in rat retina during circadian. The present investigation suggests that hnRNP-R may play roles in retinal development and light-elicited cellular activities.

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Section: Discussionsupporting

confidence: 51%

The Expression Pattern of Heterogeneous Nuclear Ribonucleoprotein R in Rat Retina

et al. 2008

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“…This complexity raises the obvious question of whether some feature of the hnRNP K pathway is responsible for the failure of optic axons to regenerate in mammals. Consistent with playing an important role in developing mammalian neurons, hnRNP K is more widely expressed in the embryonic rat brain than in the mature brain (Blanchette et al, 2006). It seems likely that its role in developing rodent brain is similar to that in axon outgrowth in Xenopus, since rodent and frog hnRNP Ks share extensive sequence identity (Bomsztyk et al, 2004) along with many key RNA targets, including type IV neurofilaments and GAP-43 (Irwin et al, 1997;Szaro, 2004, 2008).…”

Section: Discussionmentioning

confidence: 96%

Heterogeneous Nuclear Ribonucleoprotein K, an RNA-Binding Protein, Is Required for Optic Axon Regeneration inXenopus laevis

Liu

Yu²,

Deaton³

et al. 2012

J. Neurosci.

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Axotomized optic axons of Xenopus laevis, in contrast to those of mammals, retain their ability to regenerate throughout life. To better understand the molecular basis for this successful regeneration, we focused on the role of an RNA-binding protein, heterogeneous nuclear ribonucleoprotein (hnRNP) K, because it is required for axonogenesis during development and because several of its RNA targets are under strong post-transcriptional control during regeneration. At 11 d after optic nerve crush, hnRNP K underwent significant translocation into the nucleus of retinal ganglion cells (RGCs), indicating that the protein became activated during regeneration. To suppress its expression, we intravitreously injected an antisense Vivo-Morpholino oligonucleotide targeting hnRNP K. In uninjured eyes, it efficiently knocked down hnRNP K expression in only the RGCs, without inducing either an axotomy response or axon degeneration. After optic nerve crush, staining for multiple markers of regenerating axons showed no regrowth of axons beyond the lesion site with hnRNP K knockdown. RGCs nonetheless responded to the injury by increasing expression of multiple growthassociated RNAs and experienced no additional neurodegeneration above that normally seen with optic nerve injury. At the molecular level, hnRNP K knockdown during regeneration inhibited protein, but not mRNA, expression of several known hnRNP K RNA targets (NF-M, GAP-43) by compromising their efficient nuclear transport and disrupting their loading onto polysomes for translation. Our study therefore provides evidence of a novel post-transcriptional regulatory pathway orchestrated by hnRNP K that is essential for successful CNS axon regeneration.

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“…It is a member of a family of triple K-homology (KH) RNA-binding domain RNPs, which includes hnRNPs E1 and E2 and the Nova RNA-binding proteins (Buckanovich et al, 1993;Buckanovich et al, 1996;Lewis et al, 1999;Nakagawa et al, 1986). Although hnRNP K is abundantly expressed in neurons (Blanchette et al, 2006;Liu et al, 2008;Thyagarajan and Szaro, 2004), its cellular functions are known mostly from studies in cell lines, which indicate that it shuttles between the nucleus and cytoplasm and participates in multiple aspects of RNA metabolism, from splicing and nuclear export to translation and turnover. As the substrate of numerous kinases, hnRNP K is ideally suited for coupling the fates of its RNA targets with cell signaling (Adolph et al, 2007;Collier et al, 1998;Habelhah et al, 2001;Mikula et al, 2006;Ostareck-Lederer et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

Liu

Szaro

2011

Development

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SUMMARYThe RNA-binding protein, hnRNP K, is essential for axonogenesis. Suppressing its expression in Xenopus embryos yields terminally specified neurons with severely disorganized microtubules, microfilaments and neurofilaments, raising the hypothesis that hnRNP K post-transcriptionally regulates multiple transcripts of proteins that organize the axonal cytoskeleton. To identify downstream candidates for this regulation, RNAs that co-immunoprecipitated from juvenile brain with hnRNP K were identified on microarrays. A substantial number of these transcripts were linked to the cytoskeleton and to intracellular localization, trafficking and transport. Injection into embryos of a non-coding RNA bearing multiple copies of an hnRNP K RNA-binding consensus sequence found within these transcripts largely phenocopied hnRNP K knockdown, further supporting the idea that it regulates axonogenesis through its binding to downstream target RNAs. For further study of regulation by hnRNP K of the cytoskeleton during axon outgrowth, we focused on three validated RNAs representing elements associated with all three polymers -Arp2, tau and an -internexin-like neurofilament. All three were co-regulated post-transcriptionally by hnRNP K, as hnRNP K knockdown yielded comparable defects in their nuclear export and translation but not transcription. Directly knocking down expression of all three together, but not each one individually, substantially reproduced the axonless phenotype, providing further evidence that regulation of axonogenesis by hnRNP K occurs largely through pleiotropic effects on cytoskeletal-associated targets. These experiments provide evidence that hnRNP K is the nexus of a novel post-transcriptional regulatory module controlling the synthesis of proteins that integrate all three cytoskeletal polymers to form the axon.KEY WORDS: Microtubule associated protein tau, Actin-related protein 2, -Internexin, Xenopus laevis hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

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Cell-type-specific and developmental regulation of heterogeneous nuclear ribonucleoprotein K mRNA in the rat nervous system

Cited by 14 publications

References 39 publications

The Expression Pattern of Heterogeneous Nuclear Ribonucleoprotein R in Rat Retina

The Expression Pattern of Heterogeneous Nuclear Ribonucleoprotein R in Rat Retina

Heterogeneous Nuclear Ribonucleoprotein K, an RNA-Binding Protein, Is Required for Optic Axon Regeneration inXenopus laevis

hnRNP K post-transcriptionally co-regulates multiple cytoskeletal genes needed for axonogenesis

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