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The extracellular matrix (ECM) is a pivotal component adult tissues and of many tissue-specific stem cell niches. It provides structural support and regulates niche signaling during tissue maintenance and regeneration. In many tissues, ECM remodeling depends on the regulation of MMP (matrix metalloproteinase) activity by inhibitory TIMP (tissue inhibitors of metalloproteinases) proteins. Here, we report that the only Drosophila timp gene is required for maintaining the normal organization and function of the germline stem cell niche in adult females. timp mutant ovaries show reduced levels of both Drosophila Collagen IV α chains. In addition, tissue stiffness and the cellular organization of the ovarian niche are affected in timp mutants. Finally, loss of timp impairs the ability of the germline stem cell niche to generate new cysts. Our results demonstrating a crucial role for timp in tissue organization and gamete production thus provide a link between the regulation of ECM metabolism and tissue homeostasis., This work was funded by the Spanish MINECO (Grants BFU2009-08013, BFU2012-35446 to AGR, BFU2010-16669 to MDMB and Consolider CSD-2007-00008 to MDMB and AGR), by the Junta de Andalucía (Proyecto de Excelencia P09-CVI-5058 to MDMB and AGR) and by the European Regional Development Fund (FEDER). JRP was supported by a JAE-Doc contract from the Spanish National Research Council (CSIC) and KF by a Career Development Award from the UK Medical Research Council.

Programa de Doctorado en Biotecnología, Ingeniería y Tecnología Química, Línea de Investigación: Biología del Desarrollo, Clave Programa: DBI, Código Línea: 9, This work focuses on the role(s) that the extracellular matrix has during female gametogenesis in the adult Drosophila melanogaster. The extracellular matrix has an important role in a number of morphogenetic and developmentally regulated processes such as stem cell biology and the control of organ shape. The Drosophila female develops two ovaries, each composed of 16-20 egg-producing tubes called ovarioles. Eggs chambers are generated in the germarium, formed at the anterior end of each ovariole and home to two or three Germline Stem Cells (GSCs). Stem cells often reside in specialised cellular microenvironments or niches that offer stem cells structural support. In addition, signalling between support cells and stem cells is essential to regulate stem cell proliferation and to prevent their differentiation. The extracellular matrix has a fundamental role in controlling the homeostasis of stem cell niches, as it provides physical support and conveys extracellular signals. Perlecan, a heparan sulphate proteoglycan component of the extracellular matrix, has recently attracted much interest as it has been shown to act as a modulator of intercellular signals in development and morphogenesis. In this thesis we present our studies on the role of Perlecan in the maintenance of the Drosophila female germline stem cell niche and ovariole architecture. Moreover, we report the presence of different splicing isoforms of Perlecan in the basement membrane and in the interstitial matrix deposited in the GSC niche. The production of mature eggs susceptible of fertilization requires the migration of the follicular epithelium over the underlying basement membrane, a phenomenon known as egg chamber rotation. This morphogenetic event is an example of collective migration, a process in which cells maintaining stable junctions move as coordinated groups. The cooperative behaviour of migrating cells is essential and highly regulated in embryogenesis, immunity, wound healing and tumour invasion. In our work, we have quantified the levels of the only integrin functionally active during egg rotation and of one of its ligand, the extracellular component Laminin, in developing chambers. The results presented and discussed here show that Laminin amounts in the basement membrane increase with time, while integrin levels do not change significantly. We determine that the initiation and speed of egg rotation depends on the dynamic balance of integrin-Laminin amounts. Thus, the interplay of ligand-receptor levels can drive tissue migration and determine speed of migration in vivo., Universidad Pablo de Olavide. Escuela de Doctorado