Compositional Diversity and Regulation of Type IV Collagen

Abstract

Basement membranes (BMs) are thin, protein-dense extracellular matrices that enwrap all animal tissues. Type IV collagen is a heterotrimer, composed of three alpha-chains, that self-assembles into a covalently cross-linked network within BMs. The BM type IV collagen network plays numerous crucial roles in cell signaling, mechanically supporting tissues, and facilitating unique tissue functions. Precise regulation of type IV collagen helps shape tissues and enable their varied functions, while its mis-regulation is associated with diseases such as diabetes and Alzheimer’s, and in aging. However, knowledge of how type IV collagen is regulated in vivo during development and tissue growth is limited. Here, I use genome editing, live-cell imaging, conditional RNAi, overexpression, and mass spectrometry in C. elegans to investigate type IV collagen biology and identify novel regulators of type IV collagen BM deposition and turnover. In Chapter 1, I review proteins and enzymes known to regulate type IV collagen expression, construction, trafficking, BM incorporation, and turnover. I also highlight key gaps in our knowledge and expand on why C. elegans is a powerful model to investigate these questions. In Chapter 2, I discover previously unknown diversity in type IV collagen trimer composition between tissue-specific BMs in C. elegans. In Chapter 3, I identify novel, conserved regulators of type IV collagen levels in growing tissues, using C. elegans gonad migration as a model. In Chapter 4, I comprehensively examine BM emergence during embryogenesis and identify papilin as a key regulator of type IV collagen turnover during development. Finally, in Chapter 5, I discuss future directions and how these findings augment our understanding of type IV collagen regulation.