Novel Phenotypic Elements of Type IV Collagenopathy Revealed by the Drosophila Model

Abstract

Type IV collagen is proposed to be a key molecule in the evolvement of multicellular animals by forming the architectural unit basement membrane, a specialized form of the extracellular matrix. Functions of the basement membrane include guiding organ regeneration, tissue repair, modulation of cell differentiation, apical–basal polarity identification, cell migration and adhesion, regulation of growth factor signaling gradients, maintenance of tissue architecture and compartmentalization. Type IV collagenopathy is a devastating systemic disease affecting the circulatory, renal and visual systems and the skeletal muscles. It is observed in patients carrying mutations in the COL4A1 gene, which codes for the ubiquitous basement membrane component. Col4a1 mouse mutants display the human symptoms of type IV collagenopathy. We chose the Drosophila melanogaster model as we recorded dominant, temperature-sensitive mutations in the cognate col4a1 gene of the fruit fly and demonstrated phenotypic elements which have not yet been explored in humans or in mouse models. In this paper we show a transition of the Z-discs, normally bordering each sarcomere, to the level of M-discs significantly penetrant in the mutants, uneven distribution of fused mitochondria in the Malpighian tubules of the excretory organ and a loss of sarcomere structure in the visceral muscles in the gut of mutants. Our observations demonstrate the systemic nature of the col4a1 mutations in the fruit fly. However, these traits are elements of the type IV collagen-associated pathology and may provide insights into approaches that can alleviate symptoms of the disease.

Type IV Collagen Is Essential for Proper Function of Integrin-Mediated Adhesion in Drosophila Muscle Fibers

“…We have recently reported a further phenotypic manifestation of the mutants, the ectopic assembly and transition of Z-discs the anisotropic (A) band at the level of M-discs at statistical significance in the mutants [32]. These observations collectively suggest the requirement of proper COL4A1 protein in regular integrin expression and explain female sterility of the mutants that do not lay eggs at 29 °C [9].…”