Abstract
| Original language | English |
|---|---|
| Article number | ddy426 |
| Pages (from-to) | 1403-1413 |
| Number of pages | 11 |
| Journal | Human Molecular Genetics |
| Volume | 28 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 1 May 2019 |
Keywords
- integrins
- basement membrane
- collagen
- laminin
- larva
- peptides
- zebrafish
- pathology
- merosin-deficient congenital muscular dystrophy
Cite this
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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 journal › Article › Research › peer-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 -