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Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system

Nature Neuroscience volume 4, pages 977–978 (2001)Cite this article

Abstract

We identified a protein isoform of the common neurotrophin receptor p75NTR that arises from alternative splicing of exon III in the p75NTR locus. Because this protein is left intact in the previously described p75NTR mutant mouse line1, we generated a new p75NTR mutant allele. Mice homozygous for this mutation lack both protein isoforms, display severe nervous system defects and reveal a previously unknown role of p75NTR in the formation of blood vessels.

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Figure 1: A newly identified p75NTR isoform is present in p75exonIII mutants and is eliminated after targeting of the p75NTR genomic locus in exon IV.
Figure 2: Motor and PNS defects in homozygous p75exonIV mice.
Figure 3: Vasodilation in p75exonIV embryos.

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Author notes

  1. David von Schack

    Present address: AGY Therapeutics, 290 Utah Avenue, South San Francisco, California, 94080, USA

  2. David von Schack and Elisabeth Casademunt: The first two authors contributed equally to this work

Authors and Affiliations

  1. Department of Neurobiochemistry, Max Planck Institute of Neurobiology, Am Klopferspitz 18a, Martinsried, D-82152, Germany

    David von Schack, Elisabeth Casademunt, Rüdiger Schweigreiter, Michael Meyer, Miriam Bibel & Georg Dechant

  2. Friedrich Miescher Institut for Biomedical Research, Maulbeerstr. 66, CH-Basel, Switzerland

    Rüdiger Schweigreiter & Miriam Bibel

Authors
  1. David von Schack
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  2. Elisabeth Casademunt
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  3. Rüdiger Schweigreiter
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  4. Michael Meyer
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  5. Miriam Bibel
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  6. Georg Dechant
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Corresponding author

Correspondence to Georg Dechant.

Supplementary information

Supplementary Fig. 1

s-p75NTR encodes a transmembrane protein that cannot bind neurotrophins but interacts with Trk receptors.(a )Western blot analysis of the s-p75NTR protein variant in transfected A293 cells following WGA precipitation,using an antibody raised against the intracellular domain of FL-p75NTR. While under these conditions,the FL-p75 NTR protein runs at about 81 kD,s-p75NTR protein has an apparent molecular mass of 62 kD.(b )Specific binding of neurotrophins to the splice variant protein was tested using stably transfected A293 cells expressing FL-p75NTR ,s-p75NTR or empty plasmid (A293)and iodinated neurotrophins.No specific binding to s-p75NTR could be detected for any of the neurotrophins tested at concentrations ranging from 3 x 1011M to 3 x 109M.(c )Interaction with the TrkB variant T1.Stably transfected A293 cells expressing HA-tagged TrkB.T1 were transfected with the FL-p75NTR and s-p75NTR cDNAs.TrkB.T1 was immunoprecipitated (IP)with anti-HA and s-p75 NTR was detected in the precipitates with an anti-p75NTR antibody as described (Bibel,M.,Hoppe,E.& Barde,Y.A.,EMBO J.18,616-622 1999).Interaction could also be observed between the splice variant s-p75NTR and full-length Trk receptors (data not shown).Under these conditions,s-p75NTR is predominantly expressed in a non-glycosylated form, as detected by Western blot of cell extracts (right panel),which is the predominant co-immunoprecipitated form (left panel). (JPG 39 kb)

Supplementary Fig. 2

Targeting of the p75NTR genomic locus in exon IV leads to reduced body size and posterior limb ataxia.(a )Schematic representation of p75NTR genomic locus,indicating the locations of the disruptions in p75exonIII mutant mice and in the newly created p75exonIV mutant mice.In the latter mutant, disruption of the reading frame was achieved by insertion of the pGKneo cassette in exon IV within a 5.2 Kb genomic fragment.(b )Genotypic analysis of a representative litter by RT-PCR on genomic DNA from mouse tails.(c )Wild-type and homozygous p75exonIV mutant littermates at P13 showing the difference in size at this age.Adult p75exonIV -/-mouse,displaying the characteristic over-stretching response seen in mutant mice when held from their tail.Characteristic body posture of a p75exonIV mouse with hind limb ataxia.(d )Representative cross section through the sciatic nerve of P3 wild-type (wt)and p75exonIV -/-mice. (JPG 61 kb)

Supplementary Fig. 3

Vascular defects in p75exonIV -/-embryos.(a )Immunofluorescence localization of p75 NTR in E11.5 embryos,in relationship with the smooth muscle marker α-actin. p75NTR-immunoreactivity was consistently observed in the aortic walls of wild-type embryos,but weaker than in nervous structures in the spinal cord,DRG,and enteric plexus.The developing sympathetic chain was labeled.As expected, mutant p75exonIV embryos did not show any p75NTR-immunoreactivity,while some α-actin labeling was preserved.Sc:spinal cord;n:notochord;a:aorta;e:esophagus;ens:enteric nervous system.(b ) Representative litter at E15.5.The three homozygous mutant embryos of this litter can be easily identified by the presence of cerebral hemorrhages (indicated by arrows)induced by gentle pressure on the heads before genotyping. (JPG 49 kb)

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von Schack, D., Casademunt, E., Schweigreiter, R. et al. Complete ablation of the neurotrophin receptor p75NTR causes defects both in the nervous and the vascular system. Nat Neurosci 4, 977–978 (2001). https://doi.org/10.1038/nn730

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