CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos

Chris Mahony, Scott McMenemy, Alexandra J Rafipay, Shaunna-Leigh Beedie, Lucas Rosa Fraga, Michael Gutschow, William D. Figg, Lynda Erskine, Neil Vargesson (Corresponding Author)

Research output: Contribution to journalArticle

4 Citations (Scopus)
4 Downloads (Pure)

Abstract

Thalidomide notoriously caused severe birth defects, particularly to the limbs, in those exposed in utero following maternal use of the drug to treat morning sickness. How the drug caused these birth defects remains unclear. Many theories have been proposed including actions on the forming blood vessels. However, thalidomide survivors also have altered nerve patterns and the drug is known for its neurotoxic actions in adults following prolonged use. We have previously shown that CPS49, an anti-angiogenic analog of thalidomide, causes a range of limb malformations in a time-sensitive manner in chicken embryos. Here we investigated whether CPS49 also is neurotoxic and whether effects on nerve development impact upon limb development. We found that CPS49 is neurotoxic, just like thalidomide, and can cause some neuronal loss late developing chicken limbs, but only when the limb is already innervated. However, CPS49 exposure does not cause defects in limb size when added to late developing chicken limbs. In contrast, in early limb buds which are not innervated, CPS49 exposure affects limb area significantly. To investigate in more detail the role of neurotoxicity and its impact on chicken limb development we inhibited nerve innervation at a range of developmental timepoints through using β-bungarotoxin. We found that neuronal inhibition or ablation before, during or after limb outgrowth and innervation does not result in obvious limb cartilage patterning or number changes. We conclude that while CPS49 is neurotoxic, given the late innervation of the developing limb, and that neuronal inhibition/ablation throughout limb development does not cause similar limb patterning anomalies to those seen in thalidomide survivors, nerve defects are not the primary underlying cause of the severe limb patterning defects induced by CPS49/thalidomide.
Original languageEnglish
Pages (from-to)568-574
Number of pages7
JournalJournal of Anatomy
Volume232
Issue number4
Early online date10 Oct 2017
DOIs
Publication statusPublished - 1 Mar 2018

Fingerprint

neurotoxicity
limbs (animal)
limb
embryo
Chickens
embryo (animal)
Embryonic Structures
Extremities
chickens
anomaly
Thalidomide
defect
nerve tissue
innervation
drug
drugs
ablation
Morning Sickness
Pharmaceutical Preparations
limb bud

Keywords

  • thalidomide embryopathy
  • β-bungarotoxin
  • neurite growth
  • retinal explants
  • thalidomide analog

Cite this

Mahony, C., McMenemy, S., Rafipay, A. J., Beedie, S-L., Rosa Fraga, L., Gutschow, M., ... Vargesson, N. (2018). CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos. Journal of Anatomy, 232(4), 568-574. https://doi.org/10.1111/joa.12712

CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos. / Mahony, Chris; McMenemy, Scott; Rafipay, Alexandra J; Beedie, Shaunna-Leigh; Rosa Fraga, Lucas; Gutschow, Michael; Figg, William D.; Erskine, Lynda; Vargesson, Neil (Corresponding Author).

In: Journal of Anatomy, Vol. 232, No. 4, 01.03.2018, p. 568-574.

Research output: Contribution to journalArticle

Mahony, C, McMenemy, S, Rafipay, AJ, Beedie, S-L, Rosa Fraga, L, Gutschow, M, Figg, WD, Erskine, L & Vargesson, N 2018, 'CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos', Journal of Anatomy, vol. 232, no. 4, pp. 568-574. https://doi.org/10.1111/joa.12712
Mahony C, McMenemy S, Rafipay AJ, Beedie S-L, Rosa Fraga L, Gutschow M et al. CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos. Journal of Anatomy. 2018 Mar 1;232(4):568-574. https://doi.org/10.1111/joa.12712
Mahony, Chris ; McMenemy, Scott ; Rafipay, Alexandra J ; Beedie, Shaunna-Leigh ; Rosa Fraga, Lucas ; Gutschow, Michael ; Figg, William D. ; Erskine, Lynda ; Vargesson, Neil. / CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos. In: Journal of Anatomy. 2018 ; Vol. 232, No. 4. pp. 568-574.
@article{9708f9496ba9426da9ca47291fc97d49,
title = "CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos",
abstract = "Thalidomide notoriously caused severe birth defects, particularly to the limbs, in those exposed in utero following maternal use of the drug to treat morning sickness. How the drug caused these birth defects remains unclear. Many theories have been proposed including actions on the forming blood vessels. However, thalidomide survivors also have altered nerve patterns and the drug is known for its neurotoxic actions in adults following prolonged use. We have previously shown that CPS49, an anti-angiogenic analog of thalidomide, causes a range of limb malformations in a time-sensitive manner in chicken embryos. Here we investigated whether CPS49 also is neurotoxic and whether effects on nerve development impact upon limb development. We found that CPS49 is neurotoxic, just like thalidomide, and can cause some neuronal loss late developing chicken limbs, but only when the limb is already innervated. However, CPS49 exposure does not cause defects in limb size when added to late developing chicken limbs. In contrast, in early limb buds which are not innervated, CPS49 exposure affects limb area significantly. To investigate in more detail the role of neurotoxicity and its impact on chicken limb development we inhibited nerve innervation at a range of developmental timepoints through using β-bungarotoxin. We found that neuronal inhibition or ablation before, during or after limb outgrowth and innervation does not result in obvious limb cartilage patterning or number changes. We conclude that while CPS49 is neurotoxic, given the late innervation of the developing limb, and that neuronal inhibition/ablation throughout limb development does not cause similar limb patterning anomalies to those seen in thalidomide survivors, nerve defects are not the primary underlying cause of the severe limb patterning defects induced by CPS49/thalidomide.",
keywords = "thalidomide embryopathy, β-bungarotoxin, neurite growth, retinal explants, thalidomide analog",
author = "Chris Mahony and Scott McMenemy and Rafipay, {Alexandra J} and Shaunna-Leigh Beedie and {Rosa Fraga}, Lucas and Michael Gutschow and Figg, {William D.} and Lynda Erskine and Neil Vargesson",
note = "The authors thank Elizabeth Kilby and Susan Reijntes for preliminary studies. CM was funded by a University of Aberdeen PhD studentship; AJR (n{\'e}e Diamond) was funded through a BBSRC EastBio DTP PhD Award; S-L B was funded by a Wellcome Trust/NIH PhD Studentship; SM was funded by a Siddall PhD Scholarship Award; LRF was funded by the Science Without Borders PhD Scheme.",
year = "2018",
month = "3",
day = "1",
doi = "10.1111/joa.12712",
language = "English",
volume = "232",
pages = "568--574",
journal = "Journal of Anatomy",
issn = "0021-8782",
publisher = "Wiley-Blackwell",
number = "4",

}

TY - JOUR

T1 - CPS49-induced neurotoxicity does not cause limb patterning anomalies in developing chicken embryos

AU - Mahony, Chris

AU - McMenemy, Scott

AU - Rafipay, Alexandra J

AU - Beedie, Shaunna-Leigh

AU - Rosa Fraga, Lucas

AU - Gutschow, Michael

AU - Figg, William D.

AU - Erskine, Lynda

AU - Vargesson, Neil

N1 - The authors thank Elizabeth Kilby and Susan Reijntes for preliminary studies. CM was funded by a University of Aberdeen PhD studentship; AJR (née Diamond) was funded through a BBSRC EastBio DTP PhD Award; S-L B was funded by a Wellcome Trust/NIH PhD Studentship; SM was funded by a Siddall PhD Scholarship Award; LRF was funded by the Science Without Borders PhD Scheme.

PY - 2018/3/1

Y1 - 2018/3/1

N2 - Thalidomide notoriously caused severe birth defects, particularly to the limbs, in those exposed in utero following maternal use of the drug to treat morning sickness. How the drug caused these birth defects remains unclear. Many theories have been proposed including actions on the forming blood vessels. However, thalidomide survivors also have altered nerve patterns and the drug is known for its neurotoxic actions in adults following prolonged use. We have previously shown that CPS49, an anti-angiogenic analog of thalidomide, causes a range of limb malformations in a time-sensitive manner in chicken embryos. Here we investigated whether CPS49 also is neurotoxic and whether effects on nerve development impact upon limb development. We found that CPS49 is neurotoxic, just like thalidomide, and can cause some neuronal loss late developing chicken limbs, but only when the limb is already innervated. However, CPS49 exposure does not cause defects in limb size when added to late developing chicken limbs. In contrast, in early limb buds which are not innervated, CPS49 exposure affects limb area significantly. To investigate in more detail the role of neurotoxicity and its impact on chicken limb development we inhibited nerve innervation at a range of developmental timepoints through using β-bungarotoxin. We found that neuronal inhibition or ablation before, during or after limb outgrowth and innervation does not result in obvious limb cartilage patterning or number changes. We conclude that while CPS49 is neurotoxic, given the late innervation of the developing limb, and that neuronal inhibition/ablation throughout limb development does not cause similar limb patterning anomalies to those seen in thalidomide survivors, nerve defects are not the primary underlying cause of the severe limb patterning defects induced by CPS49/thalidomide.

AB - Thalidomide notoriously caused severe birth defects, particularly to the limbs, in those exposed in utero following maternal use of the drug to treat morning sickness. How the drug caused these birth defects remains unclear. Many theories have been proposed including actions on the forming blood vessels. However, thalidomide survivors also have altered nerve patterns and the drug is known for its neurotoxic actions in adults following prolonged use. We have previously shown that CPS49, an anti-angiogenic analog of thalidomide, causes a range of limb malformations in a time-sensitive manner in chicken embryos. Here we investigated whether CPS49 also is neurotoxic and whether effects on nerve development impact upon limb development. We found that CPS49 is neurotoxic, just like thalidomide, and can cause some neuronal loss late developing chicken limbs, but only when the limb is already innervated. However, CPS49 exposure does not cause defects in limb size when added to late developing chicken limbs. In contrast, in early limb buds which are not innervated, CPS49 exposure affects limb area significantly. To investigate in more detail the role of neurotoxicity and its impact on chicken limb development we inhibited nerve innervation at a range of developmental timepoints through using β-bungarotoxin. We found that neuronal inhibition or ablation before, during or after limb outgrowth and innervation does not result in obvious limb cartilage patterning or number changes. We conclude that while CPS49 is neurotoxic, given the late innervation of the developing limb, and that neuronal inhibition/ablation throughout limb development does not cause similar limb patterning anomalies to those seen in thalidomide survivors, nerve defects are not the primary underlying cause of the severe limb patterning defects induced by CPS49/thalidomide.

KW - thalidomide embryopathy

KW - β-bungarotoxin

KW - neurite growth

KW - retinal explants

KW - thalidomide analog

U2 - 10.1111/joa.12712

DO - 10.1111/joa.12712

M3 - Article

VL - 232

SP - 568

EP - 574

JO - Journal of Anatomy

JF - Journal of Anatomy

SN - 0021-8782

IS - 4

ER -