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PMID:23610558

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Citation

Kelly, CE, Thymiakou, E, Dixon, JE, Tanaka, S, Godwin, J and Episkopou, V (2013) Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor axon extension. PLoS Biol. 11:e1001538

Abstract

Little is known about extrinsic signals required for the advancement of motor neuron (MN) axons, which extend over long distances in the periphery to form precise connections with target muscles. Here we present that Rnf165 (Arkadia-like; Arkadia2; Ark2C) is expressed specifically in the nervous system and that its loss in mice causes motor innervation defects that originate during development and lead to wasting and death before weaning. The defects range from severe reduction of motor axon extension as observed in the dorsal forelimb to shortening of presynaptic branches of the phrenic nerve, as observed in the diaphragm. Molecular functional analysis showed that in the context of the spinal cord Ark2C enhances transcriptional responses of the Smad1/5/8 effectors, which are activated (phosphorylated) downstream of Bone Morphogenetic Protein (BMP) signals. Consistent with Ark2C-modulated BMP signaling influencing motor axons, motor pools in the spinal cord were found to harbor phosphorylated Smad1/5/8 (pSmad) and treatment of primary MN with BMP inhibitor diminished axon length. In addition, genetic reduction of BMP-Smad signaling in Ark2C (+/-) mice caused the emergence of Ark2C (-/-) -like dorsal forelimb innervation deficits confirming that enhancement of BMP-Smad responses by Ark2C mediates efficient innervation. Together the above data reveal an involvement of BMP-Smad signaling in motor axon advancement.

Links

PubMed PMC3627648 Online version:10.1371/journal.pbio.1001538

Keywords

Animals; Axons/physiology; Body Patterning; Bone Morphogenetic Proteins/physiology; Cell Enlargement; Forelimb/innervation; Gene Expression; HEK293 Cells; Humans; Mice; Mice, 129 Strain; Mice, Knockout; Motor Neurons/physiology; Muscle, Skeletal/innervation; Muscular Atrophy/genetics; Mutagenesis, Insertional; Nerve Tissue Proteins/genetics; Nerve Tissue Proteins/metabolism; Phenotype; Phrenic Nerve/pathology; Proteolysis; Signal Transduction; Smad Proteins/physiology; Spinal Cord/metabolism; Transcriptional Activation; Ubiquitin-Protein Ligases/genetics; Ubiquitin-Protein Ligases/metabolism; Ubiquitination

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

MOUSE:RN165

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q15797
UniProtKB:Q99717

F

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0030513: positive regulation of BMP signaling pathway

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5516581

P

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0035136: forelimb morphogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5516581

P

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0030163: protein catabolic process

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0010259: multicellular organism aging

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5516581

P

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0000209: protein polyubiquitination

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0007409: axonogenesis

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5516581

P

Seeded From UniProt

complete

MOUSE:RN165

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0008045: motor neuron axon guidance

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5516581

P

Seeded From UniProt

complete

MOUSE:RN165

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:RN165

enables

GO:0061630: ubiquitin protein ligase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0060384: innervation

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5516581

P

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0060173: limb development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:1095407

P

Seeded From UniProt

complete

MOUSE:RN165

acts_upstream_of_or_within

GO:0061061: muscle structure development

ECO:0000315: mutant phenotype evidence used in manual assertion

MGI:MGI:5516581

P

Seeded From UniProt

complete

MOUSE:SMAD6

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:O43541

C

Seeded From UniProt

complete

HUMAN:SKI

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SKI

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q6ZSG1

F

Seeded From UniProt

complete

HUMAN:SKIL

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:FOXP1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

MOUSE:SKIL

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12757

C

Seeded From UniProt

complete

MOUSE:SKI

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12755

C

Seeded From UniProt

complete

HUMAN:RN165

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P12755

F

Seeded From UniProt

complete

MOUSE:MNX1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD1

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD5

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD6

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:SMAD7

part_of

GO:0032991: protein-containing complex

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BMP4

involved_in

GO:0032092: positive regulation of protein binding

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BMP4

acts_upstream_of_or_within

GO:0032092: positive regulation of protein binding

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:P12644

P

Seeded From UniProt

complete

MOUSE:BMPR2

acts_upstream_of_or_within

GO:0060173: limb development

ECO:0000316: genetic interaction evidence used in manual assertion

MGI:MGI:2444521

P

Seeded From UniProt

complete

MOUSE:SMAD1

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q15797

C

Seeded From UniProt

complete

MOUSE:SMAD5

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:Q99717

C

Seeded From UniProt

complete

MOUSE:SMAD7

part_of

GO:0032991: protein-containing complex

ECO:0000266: sequence orthology evidence used in manual assertion

UniProtKB:O15105

C

Seeded From UniProt

complete

MOUSE:ISL1

part_of

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

Notes

See also

References

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