RGD inhibition of itgb1 ameliorates laminin-a2 deficient zebrafish fibre pathology

Alasdair J. Wood, Naomi Cohen, Veronica Joshi, Mei Li, Adam Costin, Lucy Hersey, Emily A. McKaige, Jessica D. Manneken, Carmen Sonntag, Lee Miles, Ashley Siegel, Peter D. Currie

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Deficiency of muscle basement membrane (MBM) component laminin-α2 leads to muscular dystrophy congenital type 1A (MDC1A), a currently untreatable myopathy. Laminin--α2 has two main binding partners within the MBM, dystroglycan and integrin. Integrins coordinate both cell adhesion and signalling; however, there is little mechanistic insight into integrin’s function at the MBM. In order to study integrin’s role in basement membrane development and how this relates to the MBM’s capacity to handle force, an itgβ1.b−/− zebrafish line was created. Histological examination revealed increased extracellular matrix (ECM) deposition at the MBM in the itgβ1.b−/− fish when compared with controls. Surprisingly, both laminin and collagen proteins were found to be increased in expression at the MBM of the itgβ1.b−/− larvae when compared with controls. This increase in ECM components resulted in a decrease in myotomal elasticity as determined by novel passive force analyses. To determine if it was possible to control ECM deposition at the MBM by manipulating integrin activity, RGD peptide, a potent inhibitor of integrin-β1, was injected into a zebrafish model of MDC1A. As postulated an increase in laminin and collagen was observed in the lama2−/− mutant MBM. Importantly, there was also an improvement in fibre stability at the MBM, judged by a reduction in fibre pathology. These results therefore show that blocking ITGβ1 signalling increases ECM deposition at the MBM, a process that could be potentially exploited for treatment of MDC1A.
Original languageEnglish
Article numberddy426
Pages (from-to)1403-1413
Number of pages11
JournalHuman Molecular Genetics
Volume28
Issue number9
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • integrins
  • basement membrane
  • collagen
  • laminin
  • larva
  • peptides
  • zebrafish
  • pathology
  • merosin-deficient congenital muscular dystrophy

Cite this

Wood, Alasdair J. ; Cohen, Naomi ; Joshi, Veronica ; Li, Mei ; Costin, Adam ; Hersey, Lucy ; McKaige, Emily A. ; Manneken, Jessica D. ; Sonntag, Carmen ; Miles, Lee ; Siegel, Ashley ; Currie, Peter D. / RGD inhibition of itgb1 ameliorates laminin-a2 deficient zebrafish fibre pathology. In: Human Molecular Genetics. 2019 ; Vol. 28, No. 9. pp. 1403-1413.
@article{002821e163694184a2d3040ac92dbe4e,
title = "RGD inhibition of itgb1 ameliorates laminin-a2 deficient zebrafish fibre pathology",
abstract = "Deficiency of muscle basement membrane (MBM) component laminin-α2 leads to muscular dystrophy congenital type 1A (MDC1A), a currently untreatable myopathy. Laminin--α2 has two main binding partners within the MBM, dystroglycan and integrin. Integrins coordinate both cell adhesion and signalling; however, there is little mechanistic insight into integrin’s function at the MBM. In order to study integrin’s role in basement membrane development and how this relates to the MBM’s capacity to handle force, an itgβ1.b−/− zebrafish line was created. Histological examination revealed increased extracellular matrix (ECM) deposition at the MBM in the itgβ1.b−/− fish when compared with controls. Surprisingly, both laminin and collagen proteins were found to be increased in expression at the MBM of the itgβ1.b−/− larvae when compared with controls. This increase in ECM components resulted in a decrease in myotomal elasticity as determined by novel passive force analyses. To determine if it was possible to control ECM deposition at the MBM by manipulating integrin activity, RGD peptide, a potent inhibitor of integrin-β1, was injected into a zebrafish model of MDC1A. As postulated an increase in laminin and collagen was observed in the lama2−/− mutant MBM. Importantly, there was also an improvement in fibre stability at the MBM, judged by a reduction in fibre pathology. These results therefore show that blocking ITGβ1 signalling increases ECM deposition at the MBM, a process that could be potentially exploited for treatment of MDC1A.",
keywords = "integrins, basement membrane, collagen, laminin, larva, peptides, zebrafish, pathology, merosin-deficient congenital muscular dystrophy",
author = "Wood, {Alasdair J.} and Naomi Cohen and Veronica Joshi and Mei Li and Adam Costin and Lucy Hersey and McKaige, {Emily A.} and Manneken, {Jessica D.} and Carmen Sonntag and Lee Miles and Ashley Siegel and Currie, {Peter D.}",
year = "2019",
month = "5",
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doi = "10.1093/hmg/ddy426",
language = "English",
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Wood, AJ, Cohen, N, Joshi, V, Li, M, Costin, A, Hersey, L, McKaige, EA, Manneken, JD, Sonntag, C, Miles, L, Siegel, A & Currie, PD 2019, 'RGD inhibition of itgb1 ameliorates laminin-a2 deficient zebrafish fibre pathology', Human Molecular Genetics, vol. 28, no. 9, ddy426, pp. 1403-1413. https://doi.org/10.1093/hmg/ddy426

RGD inhibition of itgb1 ameliorates laminin-a2 deficient zebrafish fibre pathology. / Wood, Alasdair J.; Cohen, Naomi; Joshi, Veronica; Li, Mei; Costin, Adam; Hersey, Lucy; McKaige, Emily A.; Manneken, Jessica D.; Sonntag, Carmen; Miles, Lee; Siegel, Ashley; Currie, Peter D.

In: Human Molecular Genetics, Vol. 28, No. 9, ddy426, 01.05.2019, p. 1403-1413.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - RGD inhibition of itgb1 ameliorates laminin-a2 deficient zebrafish fibre pathology

AU - Wood, Alasdair J.

AU - Cohen, Naomi

AU - Joshi, Veronica

AU - Li, Mei

AU - Costin, Adam

AU - Hersey, Lucy

AU - McKaige, Emily A.

AU - Manneken, Jessica D.

AU - Sonntag, Carmen

AU - Miles, Lee

AU - Siegel, Ashley

AU - Currie, Peter D.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - Deficiency of muscle basement membrane (MBM) component laminin-α2 leads to muscular dystrophy congenital type 1A (MDC1A), a currently untreatable myopathy. Laminin--α2 has two main binding partners within the MBM, dystroglycan and integrin. Integrins coordinate both cell adhesion and signalling; however, there is little mechanistic insight into integrin’s function at the MBM. In order to study integrin’s role in basement membrane development and how this relates to the MBM’s capacity to handle force, an itgβ1.b−/− zebrafish line was created. Histological examination revealed increased extracellular matrix (ECM) deposition at the MBM in the itgβ1.b−/− fish when compared with controls. Surprisingly, both laminin and collagen proteins were found to be increased in expression at the MBM of the itgβ1.b−/− larvae when compared with controls. This increase in ECM components resulted in a decrease in myotomal elasticity as determined by novel passive force analyses. To determine if it was possible to control ECM deposition at the MBM by manipulating integrin activity, RGD peptide, a potent inhibitor of integrin-β1, was injected into a zebrafish model of MDC1A. As postulated an increase in laminin and collagen was observed in the lama2−/− mutant MBM. Importantly, there was also an improvement in fibre stability at the MBM, judged by a reduction in fibre pathology. These results therefore show that blocking ITGβ1 signalling increases ECM deposition at the MBM, a process that could be potentially exploited for treatment of MDC1A.

AB - Deficiency of muscle basement membrane (MBM) component laminin-α2 leads to muscular dystrophy congenital type 1A (MDC1A), a currently untreatable myopathy. Laminin--α2 has two main binding partners within the MBM, dystroglycan and integrin. Integrins coordinate both cell adhesion and signalling; however, there is little mechanistic insight into integrin’s function at the MBM. In order to study integrin’s role in basement membrane development and how this relates to the MBM’s capacity to handle force, an itgβ1.b−/− zebrafish line was created. Histological examination revealed increased extracellular matrix (ECM) deposition at the MBM in the itgβ1.b−/− fish when compared with controls. Surprisingly, both laminin and collagen proteins were found to be increased in expression at the MBM of the itgβ1.b−/− larvae when compared with controls. This increase in ECM components resulted in a decrease in myotomal elasticity as determined by novel passive force analyses. To determine if it was possible to control ECM deposition at the MBM by manipulating integrin activity, RGD peptide, a potent inhibitor of integrin-β1, was injected into a zebrafish model of MDC1A. As postulated an increase in laminin and collagen was observed in the lama2−/− mutant MBM. Importantly, there was also an improvement in fibre stability at the MBM, judged by a reduction in fibre pathology. These results therefore show that blocking ITGβ1 signalling increases ECM deposition at the MBM, a process that could be potentially exploited for treatment of MDC1A.

KW - integrins

KW - basement membrane

KW - collagen

KW - laminin

KW - larva

KW - peptides

KW - zebrafish

KW - pathology

KW - merosin-deficient congenital muscular dystrophy

U2 - 10.1093/hmg/ddy426

DO - 10.1093/hmg/ddy426

M3 - Article

VL - 28

SP - 1403

EP - 1413

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 9

M1 - ddy426

ER -