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Novel Kidins220/ARMS Splice Isoforms: Potential Specific Regulators of Neuronal and Cardiovascular Development.

Schmieg N, Thomas C, Yabe A, Lynch DS, Iglesias T, Chakravarty P, Schiavo G - PLoS ONE (2015)

Bottom Line: The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33.Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript.Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neuropathobiology Laboratory, Sobell Department of Motor Neuroscience & Movement Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, United Kingdom; The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, United Kingdom.

ABSTRACT
Kidins220/ARMS is a transmembrane protein playing a crucial role in neuronal and cardiovascular development. Kidins220/ARMS is a downstream target of neurotrophin receptors and interacts with several signalling and trafficking factors. Through computational modelling, we found two potential sites for alternative splicing of Kidins220/ARMS. The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33. Here we describe the conserved occurrence of several Kidins220/ARMS splice isoforms at RNA and protein levels. Kidins220/ARMS splice isoforms display spatio-temporal regulation during development with distinct patterns in different neuronal populations. Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript. Remarkably, alternative terminal exon splicing generates Kidins220/ARMS variants with distinct cellular localisation: Kidins220/ARMS containing exon 32 is targeted to the plasma membrane and neurite tips, whereas Kidins220/ARMS without exon 33 mainly clusters the full-length protein in a perinuclear intracellular compartment in PC12 cells and primary neurons, leading to a change in neurotrophin receptor expression. Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.

No MeSH data available.


Related in: MedlinePlus

Developmental-specific expression of Kidins220 alternative splice isoforms in mouse brain.(A-B) RT-PCR analyses for exons encoding the amino-terminus of Kidins220 and between exons 24 and 30 (A), and for alternative terminal exon splicing (B) were carried out on mouse brains at different developmental stages, starting from embryonic stage E13.5 up to postnatal stage P64. The analysis at the latter stage includes adult male (M) and female (F) brains. N indicates PCR products obtained using primers designed to recognise exons 3 and 8. 24f-30r indicates samples obtained by amplification with primers recognising exons 24 and 30 (A). C indicates PCR products obtained using primers designed to recognise exons 31/32 and 32. 31f-33r indicates samples obtained by amplification with primers recognising exons 31 and 33 (B). The arrowhead points to appearance of Kidins220 isoform m1 (full-length) at postnatal stage P11 (A).
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pone.0129944.g004: Developmental-specific expression of Kidins220 alternative splice isoforms in mouse brain.(A-B) RT-PCR analyses for exons encoding the amino-terminus of Kidins220 and between exons 24 and 30 (A), and for alternative terminal exon splicing (B) were carried out on mouse brains at different developmental stages, starting from embryonic stage E13.5 up to postnatal stage P64. The analysis at the latter stage includes adult male (M) and female (F) brains. N indicates PCR products obtained using primers designed to recognise exons 3 and 8. 24f-30r indicates samples obtained by amplification with primers recognising exons 24 and 30 (A). C indicates PCR products obtained using primers designed to recognise exons 31/32 and 32. 31f-33r indicates samples obtained by amplification with primers recognising exons 31 and 33 (B). The arrowhead points to appearance of Kidins220 isoform m1 (full-length) at postnatal stage P11 (A).

Mentions: Since the expression levels of Kidins220 splice variants undergo dramatic changes in embryonic and adult mouse brain, we sought to investigate their regulation during development. We therefore extracted RNA from mouse brains starting at E13.5 until postnatal day 64 (P64), and after reverse transcription, amplified these samples with primers designed to recognise exon 24 and 30 (Fig 4A) and exon 31 and 33 (Fig 4B).


Novel Kidins220/ARMS Splice Isoforms: Potential Specific Regulators of Neuronal and Cardiovascular Development.

Schmieg N, Thomas C, Yabe A, Lynch DS, Iglesias T, Chakravarty P, Schiavo G - PLoS ONE (2015)

Developmental-specific expression of Kidins220 alternative splice isoforms in mouse brain.(A-B) RT-PCR analyses for exons encoding the amino-terminus of Kidins220 and between exons 24 and 30 (A), and for alternative terminal exon splicing (B) were carried out on mouse brains at different developmental stages, starting from embryonic stage E13.5 up to postnatal stage P64. The analysis at the latter stage includes adult male (M) and female (F) brains. N indicates PCR products obtained using primers designed to recognise exons 3 and 8. 24f-30r indicates samples obtained by amplification with primers recognising exons 24 and 30 (A). C indicates PCR products obtained using primers designed to recognise exons 31/32 and 32. 31f-33r indicates samples obtained by amplification with primers recognising exons 31 and 33 (B). The arrowhead points to appearance of Kidins220 isoform m1 (full-length) at postnatal stage P11 (A).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4470590&req=5

pone.0129944.g004: Developmental-specific expression of Kidins220 alternative splice isoforms in mouse brain.(A-B) RT-PCR analyses for exons encoding the amino-terminus of Kidins220 and between exons 24 and 30 (A), and for alternative terminal exon splicing (B) were carried out on mouse brains at different developmental stages, starting from embryonic stage E13.5 up to postnatal stage P64. The analysis at the latter stage includes adult male (M) and female (F) brains. N indicates PCR products obtained using primers designed to recognise exons 3 and 8. 24f-30r indicates samples obtained by amplification with primers recognising exons 24 and 30 (A). C indicates PCR products obtained using primers designed to recognise exons 31/32 and 32. 31f-33r indicates samples obtained by amplification with primers recognising exons 31 and 33 (B). The arrowhead points to appearance of Kidins220 isoform m1 (full-length) at postnatal stage P11 (A).
Mentions: Since the expression levels of Kidins220 splice variants undergo dramatic changes in embryonic and adult mouse brain, we sought to investigate their regulation during development. We therefore extracted RNA from mouse brains starting at E13.5 until postnatal day 64 (P64), and after reverse transcription, amplified these samples with primers designed to recognise exon 24 and 30 (Fig 4A) and exon 31 and 33 (Fig 4B).

Bottom Line: The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33.Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript.Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.

View Article: PubMed Central - PubMed

Affiliation: Molecular Neuropathobiology Laboratory, Sobell Department of Motor Neuroscience & Movement Disorders, UCL Institute of Neurology, University College London, London WC1N 3BG, United Kingdom; The Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, United Kingdom.

ABSTRACT
Kidins220/ARMS is a transmembrane protein playing a crucial role in neuronal and cardiovascular development. Kidins220/ARMS is a downstream target of neurotrophin receptors and interacts with several signalling and trafficking factors. Through computational modelling, we found two potential sites for alternative splicing of Kidins220/ARMS. The first is located between exon 24 and exon 29, while the second site replaces exon 32 by a short alternative terminal exon 33. Here we describe the conserved occurrence of several Kidins220/ARMS splice isoforms at RNA and protein levels. Kidins220/ARMS splice isoforms display spatio-temporal regulation during development with distinct patterns in different neuronal populations. Neurotrophin receptor stimulation in cortical and hippocampal neurons and neuroendocrine cells induces specific Kidins220/ARMS splice isoforms and alters the appearance kinetics of the full-length transcript. Remarkably, alternative terminal exon splicing generates Kidins220/ARMS variants with distinct cellular localisation: Kidins220/ARMS containing exon 32 is targeted to the plasma membrane and neurite tips, whereas Kidins220/ARMS without exon 33 mainly clusters the full-length protein in a perinuclear intracellular compartment in PC12 cells and primary neurons, leading to a change in neurotrophin receptor expression. Overall, this study demonstrates the existence of novel Kidins220/ARMS splice isoforms with unique properties, revealing additional complexity in the functional regulation of neurotrophin receptors, and potentially other signalling pathways involved in neuronal and cardiovascular development.

No MeSH data available.


Related in: MedlinePlus