MEIS1 & VASCULAR MK · Role of Meis1 in the embryonic megakaryocyte lineage and vascular development
7РП — „Хора“ (Действия „Мария Кюри“)
- Период
- 2010-06-01 → 2012-05-31
- Финансиране от ЕС
- 153 917 €
- Участници
- 1
- Схема
- MC-IEF
Линиите свързват координатора с партньорите.
Накратко на български
Ролята на протеина Meis1 и CD41-положителните клетки се анализира при развитието на кръвоносните съдове чрез модели с мишки и зебрни рибки. Това помага да се разбере защо определени генетични мутации пречат на правилното формиране на лимфната система.
Кратко обяснение, генерирано от езиков модел по текста на CORDIS. Оригиналът е по-долу.
Резултати накратко
Role of Meis1 in the embryonic megakaryocyte lineage and vascular development
Project context and objectives Our objective is to understand the role of the thrombocytic lineage in the development of the vasculature. In the reporting period we have established zebrafish as an equivalent animal model to mice for the analysis of the thrombocytic/embryonic megakaryocyte lineage function during vascular development, with the added advantage of real-time live imaging during embryonic development. We carried out a multi-disciplinary project, using genetic engineering, transgenic mice and fish animal models, genetics, in-vivo imaging, cell purification and transplantation to improve our understanding of the role of CD41 positive cells in the maturation of the vasculature. Project results Our top result can be described as a novel, not yet described, interaction between CD41 positive cells and venous sprouts that in turn will give origin to nascent lymphatics. As such, this provided a clear and testable hypothesis for why several mutations that impair the development of blood lineages, more specifically of CD41 positive cells, also impair the formation of the lymphatic vasculature. Initially, we used Meis1 loss of function as a model for the depletion of the thrombocytic/embryonic megakaryocyte lineage in both fish and mice. The only hematopoietic defect found in Meis1 null mice is the absence of megakaryocytes and derived platelets; Meis1 null mice die between embryonic day 11.5 and 14.5 with internal haemorrhages and blood-filled lymphatics. Our novel interaction of CD41 cells with venous sprouts, which we first recorded in live time-lapse confocal microscopy in zebrafish embryos, simultaneously pinpoints the lineage responsible for the defects and a possible mechanism of action, thereby accomplishing a major objective of our proposal. To further our understanding, we continued to probe this cellular interaction between CD41 cells and the endothelium, now with time and lineage controlled loss-of-function approaches and the use of genetic binary systems, such as the CRE-loxP and Gal4:UAS strategies that enable the depletion of the thrombocytic lineage while imaging CD41 positive cells and endothelial cell behaviour. The potential impact of this project is to identify a cell population capable of regulating the behaviour and fate of endothelial cells, which will open the door to clinical applications, and possible ways to target the vascular system and its regulation.
Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз
Цел на проекта
The main aim of the present project is to provide the first description of embryonic megakaryocyte function during vascular development and maintenance. The recent description of embryonic megakaryocytes existence together with the presence of vascular defects in all mouse mutant models that lack embryonic megakaryocytes suggests that a cellular interaction between embryonic megakaryocytes and endothelium is essential for the correct patterning and stability of the vasculature. The vascular system is the first organ to become functional in the embryo and its regulatory mechanisms are of ultimate medical importance in cancer, development, homeostasis, healing and regeneration. Likewise, blood and endothelium develop in close association and it is surprising to realize how little we know on how specific haematopoietic lineages support the development of a functional vasculature. We will address this important issue by characterizing the function of Meis1 in the megakaryocytic lineage and of the megakaryocytic lineage in vascularization. Meis1 mutant mice are the only known mutant mice that lack embryonic megakaryocytes without another apparent haematopoietic deficiency. Therefore, Meis1 null mice present a unique opportunity to investigate this common denominator – absence of megakaryocytes – on all haematopoietic mutants that present vascular defects. We will achieve this goal by: 1) a detailed characterization of the Meis1 vascular defect using histological approaches and optical projection tomography; 2) imaging the behaviour and interaction of the megakaryocyte cellular equivalents and the endothelium in live zebrafish embryos; and 3) establish the role of Meis1 and of embryonic megakaryocytes in embryonic vascularization through the targeted elimination of this lineage, the rescue of Meis1 null vascular phenotype by megakaryocyte progenitor transplantation and by the conditional reactivation of Meis function in the megakaryocytic lineage of Meis1 null embryos.
Оригинален текст от CORDIS (на английски).
Участници
- CENTRO NACIONAL DE INVESTIGACIONES CARDIOVASCULARES CARLOS III (F.S.P.) · MadridКоординаторИспания
Връзки
Данни: CORDIS, © Европейски съюз