Matrix metalloproteinases regulate ECM accumulation but not larval heart growth in Drosophila melanogaster

Abstract

The Drosophila heart provides a simple model to examine the remodelling of muscle insertions with growth, extracellular matrix (ECM) turnover, and fibrosis. Between hatching and pupation, the Drosophila heart increases in length five-fold. If major cardiac ECM components are secreted remotely, how is ECM "self assembly" regulated? We explored whether ECM proteases were required to maintain the morphology of a growing heart while the cardiac ECM expanded. An increase in expression of Drosophila's single tissue inhibitor of metalloproteinase (TIMP), or reduced function of metalloproteinase MMP2, resulted in fibrosis and ectopic deposition of two ECM Collagens; type-IV and fibrillar Pericardin. Significant accumulations of Collagen-IV (Viking) developed on the pericardium and in the lumen of the heart. Congenital defects in Pericardin deposition misdirected further assembly in the larva. Reduced metalloproteinase activity during growth also increased Pericardin fibre accumulation in ECM suspending the heart. Although MMP2 expression was required to remodel and position cardiomyocyte cell junctions, reduced MMP function did not impair expansion of the heart. A previous study revealed that MMP2 negatively regulates the size of the luminal cell surface in the embryonic heart. Cardiomyocytes align at the midline, but do not adhere to enclose a heart lumen in MMP2 mutant embryos. Nevertheless, these embryos hatch and produce viable larvae with bifurcated hearts, indicating a secondary pathway to lumen formation between ipsilateral cardiomyocytes. MMP-mediated remodelling of the ECM is required for organogenesis, and to prevent assembly of excess or ectopic ECM protein during growth. MMPs are not essential for normal growth of the Drosophila heart. Build-up of ECM proteins is also correlated with dilated cardiomyopathy (DCM) and heart failure in mammals [18,36]. Key components of the basement membrane include Laminins, the first proteins to be incorporated into the basal lamina [49,73], and the structural protein Collagen-IV [32]. Their deposition and stabilisation is guided by cell surface receptors and secreted ligands such as Dystroglycan, Perlecan, and Nidogen [43,81]. Furthermore, they can be degraded by numerous proteinases, notably matrix metalloproteinases (MMPs), which allow for local ECM specialisation, cell migration, and the release of growth factors [7]. MMPs, a class of zinc-dependent endopeptidases of the metzincin proteinase superfamily, participate in

Roles of matrix metalloproteinases in development, immunology, and ovulation in fruit Fly (Drosophila)

“…In mmp2 mutation or when MMP2 activity was reduced, an abnormally high concentration of Prc protein was observed in both cases (Hughes et al, 2020). Oppositely, overexpressed MMP2 showed a significant diminution of Prc network formation (Hughes et al, 2020).…”

“…MMP2 also performs in the distribution of heart specific collagen, pericardin (Prc) protein (Hughes et al, 2020).…”

“…In mmp2 mutation or when MMP2 activity was reduced, an abnormally high concentration of Prc protein was observed in both cases (Hughes et al, 2020). Oppositely, overexpressed MMP2 showed a significant diminution of Prc network formation (Hughes et al, 2020). Viking (Vkg), a type of collagen IV, is found at the basal and medially located apical surface, not in the apical extensions (Raza et al, 2017).…”

Research Progress of Myocardial Fibrosis and Atrial Fibrillation

“…However, studies have shown that MMP-mediated ECM remodeling is necessary for organ formation in the Drosophila model. It can also prevent excessive or ectopic ECM protein assembly during growth ( 113 ). The study is different from the above results, which may be explained by different models, or the regulation of MMP is a two-way process that plays different roles in different stages of tissue and organ development.…”

Scribbleknockdown induced metastasis tracking, identification of its associated novel molecular candidates through Proteome andin silicostudies

“…Matrix metalloproteinases (MMPs), one of the metastasis biomarker, are extracellular calcium-dependent zinc-containing proteases, which regulate many signaling pathways involved in cell differentiation, proliferation, and metastasis [6]. In humans there are 24 MMPs, of which, 7 MMPs are GPI (Glycosylphoshatidylinositol) anchored and 17 MMPs are soluble secreted proteinases [7]. Drosophila has only two MMPs proteases, soluble secreted protease MMP1, and membrane tethered protease MMP2, making it a simple model organism for study of the involvement of MMPs in tumor metastasis [8].…”