The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse

J. Martin Collinson (Lead / Corresponding author), Nils O. Lindström, Carlos Neves, Karen Wallace, Caroline Meharg, Rebecca H. Charles, Zoe K. Ross, Amy M. Fraser, Ivan Mbogo, Kadri Oras, Masaru Nakamoto, Simon Barker, Suzanne Duce, Zosia Miedzybrodzka, Neil Vargesson

Research output: Contribution to journalArticle

2 Citations (Scopus)
76 Downloads (Pure)

Abstract

Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. Thepmamutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation ofLimk1by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.

Original languageEnglish
Article numberdev160093
Pages (from-to)1-15
Number of pages15
JournalDevelopment
Volume145
Issue number3
Early online date8 Feb 2018
DOIs
Publication statusPublished - Feb 2018

Fingerprint

Charcot-Marie-Tooth Disease
Clubfoot
Lim Kinases
Motor Neurons
Sciatic Nerve
Actins
Cofilin 1
Growth Cones
Electroporation
Hindlimb
Growth
Molecular Biology
Lower Extremity
Chickens
Up-Regulation
Extremities
Pharmacology
Phenotype
Muscles
Mutation

Keywords

  • Axon guidance
  • Chicken
  • Clubfoot
  • Limb development
  • Limk1

Cite this

Collinson, J. M., Lindström, N. O., Neves, C., Wallace, K., Meharg, C., Charles, R. H., ... Vargesson, N. (2018). The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse. Development, 145(3), 1-15. [dev160093]. https://doi.org/10.1242/dev.160093
Collinson, J. Martin ; Lindström, Nils O. ; Neves, Carlos ; Wallace, Karen ; Meharg, Caroline ; Charles, Rebecca H. ; Ross, Zoe K. ; Fraser, Amy M. ; Mbogo, Ivan ; Oras, Kadri ; Nakamoto, Masaru ; Barker, Simon ; Duce, Suzanne ; Miedzybrodzka, Zosia ; Vargesson, Neil. / The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse. In: Development. 2018 ; Vol. 145, No. 3. pp. 1-15.
@article{5eb7bb6ebd10433ebd255edf2a2a7367,
title = "The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse",
abstract = "Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. Thepmamutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation ofLimk1by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.",
keywords = "Axon guidance, Chicken, Clubfoot, Limb development, Limk1",
author = "Collinson, {J. Martin} and Lindstr{\"o}m, {Nils O.} and Carlos Neves and Karen Wallace and Caroline Meharg and Charles, {Rebecca H.} and Ross, {Zoe K.} and Fraser, {Amy M.} and Ivan Mbogo and Kadri Oras and Masaru Nakamoto and Simon Barker and Suzanne Duce and Zosia Miedzybrodzka and Neil Vargesson",
note = "This study was funded by Medical Research Council project grant reference G0800901 (grant ID: 87379). C.N. was funded by the Funda{\cc}{\~a}o para a Ci{\^e}ncia e a Tecnologia (Portugal). K.O. was funded by a Gurdon Scholarship from the British Society for Developmental Biology. Z.K.R. was funded by an Anatomical Society Summer Studentship. Deposited in PMC for release after 6 months.",
year = "2018",
month = "2",
doi = "10.1242/dev.160093",
language = "English",
volume = "145",
pages = "1--15",
journal = "Development",
issn = "0950-1991",
publisher = "Company of Biologists",
number = "3",

}

Collinson, JM, Lindström, NO, Neves, C, Wallace, K, Meharg, C, Charles, RH, Ross, ZK, Fraser, AM, Mbogo, I, Oras, K, Nakamoto, M, Barker, S, Duce, S, Miedzybrodzka, Z & Vargesson, N 2018, 'The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse', Development, vol. 145, no. 3, dev160093, pp. 1-15. https://doi.org/10.1242/dev.160093

The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse. / Collinson, J. Martin (Lead / Corresponding author); Lindström, Nils O.; Neves, Carlos; Wallace, Karen; Meharg, Caroline; Charles, Rebecca H.; Ross, Zoe K.; Fraser, Amy M.; Mbogo, Ivan; Oras, Kadri; Nakamoto, Masaru; Barker, Simon; Duce, Suzanne; Miedzybrodzka, Zosia; Vargesson, Neil.

In: Development, Vol. 145, No. 3, dev160093, 02.2018, p. 1-15.

Research output: Contribution to journalArticle

TY - JOUR

T1 - The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse

AU - Collinson, J. Martin

AU - Lindström, Nils O.

AU - Neves, Carlos

AU - Wallace, Karen

AU - Meharg, Caroline

AU - Charles, Rebecca H.

AU - Ross, Zoe K.

AU - Fraser, Amy M.

AU - Mbogo, Ivan

AU - Oras, Kadri

AU - Nakamoto, Masaru

AU - Barker, Simon

AU - Duce, Suzanne

AU - Miedzybrodzka, Zosia

AU - Vargesson, Neil

N1 - This study was funded by Medical Research Council project grant reference G0800901 (grant ID: 87379). C.N. was funded by the Fundação para a Ciência e a Tecnologia (Portugal). K.O. was funded by a Gurdon Scholarship from the British Society for Developmental Biology. Z.K.R. was funded by an Anatomical Society Summer Studentship. Deposited in PMC for release after 6 months.

PY - 2018/2

Y1 - 2018/2

N2 - Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. Thepmamutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation ofLimk1by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.

AB - Genetic factors underlying the human limb abnormality congenital talipes equinovarus ('clubfoot') remain incompletely understood. The spontaneous autosomal recessive mouse 'peroneal muscular atrophy' mutant (PMA) is a faithful morphological model of human clubfoot. In PMA mice, the dorsal (peroneal) branches of the sciatic nerves are absent. In this study, the primary developmental defect was identified as a reduced growth of sciatic nerve lateral motor column (LMC) neurons leading to failure to project to dorsal (peroneal) lower limb muscle blocks. Thepmamutation was mapped and a candidate gene encoding LIM-domain kinase 1 (Limk1) identified, which is upregulated in mutant lateral LMC motor neurons. Genetic and molecular analyses showed that the mutation acts in the EphA4-Limk1-Cfl1/cofilin-actin pathway to modulate growth cone extension/collapse. In the chicken, both experimental upregulation ofLimk1by electroporation and pharmacological inhibition of actin turnover led to defects in hindlimb spinal motor neuron growth and pathfinding, and mimicked the clubfoot phenotype. The data support a neuromuscular aetiology for clubfoot and provide a mechanistic framework to understand clubfoot in humans.

KW - Axon guidance

KW - Chicken

KW - Clubfoot

KW - Limb development

KW - Limk1

UR - http://www.scopus.com/inward/record.url?scp=85042484857&partnerID=8YFLogxK

U2 - 10.1242/dev.160093

DO - 10.1242/dev.160093

M3 - Article

VL - 145

SP - 1

EP - 15

JO - Development

JF - Development

SN - 0950-1991

IS - 3

M1 - dev160093

ER -

Collinson JM, Lindström NO, Neves C, Wallace K, Meharg C, Charles RH et al. The developmental and genetic basis of 'clubfoot' in the peroneal muscular atrophy mutant mouse. Development. 2018 Feb;145(3):1-15. dev160093. https://doi.org/10.1242/dev.160093