Early development and pathologies (INSERM U833)

Geneviève NGUYEN

Using embryonic stem cell (ESC) and induced pluripotent stem (IPs) cell models, we study self-renewal, differentiation and signaling pathways controlling these processes, our aim being to develop in vitro disease models to test new drugs.
We have two major themes of research :

1. The renin-angiotensin system in early development and pathology :
- Effect of mutations of Renin gene responsible for renal tubular dysgenesis, a severe kidney malformation provoking perinatal death, on the synthesis, trafficking and enzymatic activity of mutant renin
- Role of the (pro)renin receptor (PRR) in embryonic stem cell self-renewal and early neural differentiation and in neurodevelopmental processes (proliferation, migration, differentiation) dependent on PRR signaling.

Immunofluorescence staining of (pro)renin receptor in morula and blastocyst

2. Transforming Growth Factor-beta (TGFß) receptors in vascular development and disease
TGF-β signaling is essential during vascular development. In patients, mutations in TGF-β type I receptor ALK1 and in accessory receptor endoglin are linked to autosomal dominant Hereditary Hemorrhagic Telangiectasia characterized by mucocutaneous telangiectases, thinning of the vessel walls and frequent nosebleeding. Using mouse models for HHT, we study the mechanisms underlying the vessel phenotype including loss of smooth muscle cells coverage and we generate and differentiate ESC or IPs cells from ALK1 and endoglin mutant mice to develop models for studying normal physiology and disease and as a platform for drug discovery and toxicity.

Sprouting angiogenesis using embryonic stem cell

Skin vascular network

Selected Publications 2005-2009

- Lebrin F., Srun S., Raymond K ., Martin S., van den Brink S., Freitas C., Bréant C., Mathivet T., Larrivée B., Thomas J .L., Arthur H.M., Westermann C.J., Disch F., Mager J.J., Snijder R.J., Eichmann A. & Mummery C.L. (2010), Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia. Nat Med, Apr;16(4):420-8.
- Cousin C., Bracquart D., Contrepas A., Corvol P., Muller L. & Nguyen G. (2009), Soluble form of the (pro)renin receptor generated by intracellular cleavage by furin is secreted in plasma. Hypertension, Apr 20.
- Vincent F., Bonnin P., Clemessy M., Contrerès J.O., Lamandé N., Gasc J.M., Vilar J., Hainaud P., Tobelem G., Corvol P. & Dupuy E. (2009), Angiotensinogen delays angiogenesis and tumor growth of hepatocarcinoma in transgenic mice. Cancer Res., 69(7):2853-60.
- Braam S.R., Zeinstra L., Litjens S., Ward-van Oostwaard D., van den Brink S., van Laake L ., Lebrin F., Kats P., Hochstenbach R., Passier R., Sonnenberg A. & Mummery C.L. (2008), Recombinant vitronectin is a functionally defined substrate that supports human embryonic stem cell self-renewal via alphavbeta5 integrin. Stem Cells, 26(9):2257-65.
- Burckl C.A., Danser A.H.J., Müller D.N;, Garrelds I.M;, Gasc J.M., Popova E., Plehm R., Peters J., Bader M. & Nguyen G. (2006), Elevated blood pressure and heart rate in human renin receptor transgenic rats. Hypertension, 47: 552-556.
- Van Laake L.W., Van den Driesche S., Post S., Feijen A., Jansen M.A., Driessens M.H., Mager J.J., Snijder R.J., Westermann C.J., Doevendans P.A., van Echteld C.J., ten Dijke P., Arthur H.M., Goumans M.J., Mummery C.L. & Lebrin F. (2006), Endoglin has a crucial role in blood cell-mediated vascular repair. Circulation, 114(21):2288-97.
- Ramser J., Abidi F.E., Burckle C.A., Lenski C., Toriello H., Wen G., Lubs H.A., Engert S., Stevenson R.E., Meindl A., Schwartz C.E. & Nguyen G. (2005), A unique exonic splice enhancer mutation in a family with X-linked mental retardation and epilepsy points to a novel role of the renin receptor. Hum Mol Genet 14: 1019-1027.

PEOPLE

Director :
Nguyen Genevieve, DR2 INSERM

Co-Director :
Lebrin Franck, CR1 INSERM

Professor at College de France :
Corvol Pierre

Senior researchers :
Lamandé Noël, MC CDF
Costa-Neto Claudio, MC associé CDF
Hirose Takuo, MC associé CDF

Technical staff :
Michaud Annie, ITA
Queguiner Isabelle, ITA
Martin Sabrina, ITA

Post-docs and students :
Bracquart Diane
Srun Samly
Le Naoures Cécile, Etudiante M2
Ruggiu Mathilde, Etudiante M1