Studio delle interazione genetiche che governano la linfangiogenesi in topo e zebrafish: una strategia per rivelare le basi molecolari delle patologie vascolari linfatiche

The lymphatic system is a major component of the vertebrate vasculature and plays key roles in tissue

fluid homeostasis, fat absorption, and the immune response. Lymphatic vessel function or dysfunction

contributes to the progression of several pathological conditions, such as tumor metastasis, lymphedema,

and inflammation. Despite its great biological and medical importance, lymphangiogenesis (i.e. the

growth of lymphatic vessels from pre-existing veins or lymphatics) is far less studied than blood vessel

angiogenesis. Some of the key molecules and molecular mechanisms, that govern lymphatic development

from a subpopulation of venous endothelial cells in the embryo, have been discovered, however much

remains to be elucidated. The very same molecules, that act in embryonic lymphatic development, usually

play crucial roles in pathological conditions and their characterization is thus highly relevant to human

health.



A lymphatic system, sharing morphological and molecular characteristics with the mammalian one, has

recently been discovered in zebrafish, making it an attractive new model for the study of

lymphangiogenesis relevant to human disease. The project we propose here arises from the collaborative

effort of an established Italian group at the “Universita’ degli Studi di Milano” and the teams of two

talented scientists, who recently made very important contributions to the field of lymphangiogenesis,

using mouse and zebrafish models. These groups are now located at the IMB, Australia, in the Division of

Molecular Genetics and Development, which is headed by Prof. Peter Koopman (a world leader in the field

of SOX proteins and lymphatic development).



This is a highly integrated research proposal centred on SOX18, a key transcription factor in lymphatic

differentiation, which is mutated in patients affected by HLT (Hypotrichosis-Lymphedema-Telangiectasia)

syndrome. Through a multidisciplinary approach, combining mouse and zebrafish model systems, we aim

at better defining the molecular networks that control lymphatic vascular differentiation. In the long

term, one exciting prospect of this study is to provide new molecular tools for diagnosis or treatment of

human lymphatic disorders.



In this research project, our goals are:

i) To decipher, in the zebrafish model system, the molecular network by which Sox18 orchestrates

lymphangiogenesis;

ii) To find new molecular players, by gene expression profiling in mouse and zebrafish, in conditions of

defective Sox18 function;

iii) To analyze the function of a selected number of Sox18 downstream targets in zebrafish lymphatic

development, through a functional gene-knockdown strategy with morpholinos.



We expect that the results obtained through these complementary approaches will contribute to a

substantial advancement in the basic knowledge of key regulatory pathways governing lymphangiogenesis

and their degree of evolutionary conservation.

The financing of this project will create a unique opportunity for the training of young students and post-

docs in the frame of a collaboration that puts them in contact with an exciting international environment,

from which they will certainly benefit.