An Zwijsen
Developmental Signaling
VIB Department of Molecular and Developmental Genetics, K.U.Leuven

PhD: Univ. of Antwerp, Antwerp, Belgium, '95 Postdoc: NIOB, Hubrecht Laboratory, Utrecht, The Netherlands, '95-'97 VIB Group leader since 2008

e-mail phone +32 16 33 00 06 ADDRESS

Current team members
Group leader: An Zwijsen
Ph.D. Students: Iván Moya, Mariya Dobreva, Paulo Pereira
Support personnel: Elke Maas

Keywords
mouse embryo - stem cell - amnion - cardiovascular development -TGF/Smad

Science

Cell Fate decisions governed by BMP-Smads

In the embryo, developmental processes of growth and differentiation are highly regulated programs that enable different tissues to form and embryonic cells to move from one site in the body to another. Similar processes operate also in adult tissues that undergo continues renewing, such as e.g. the skin. Moreover, cancer cells resurrect often early embryonic behavioral programs. The re-expression of early embryonic transcription factors and the formation of new blood vessels allow cancer cells to become highly proliferative, and to become invasive. The fundamental understanding of early developmental processes is therefore highly relevant to give direct insight in (malignant) disease.

The Zwijsen team is zeroing on mouse embryos no bigger than specks of dust, and asks how cells in the early mouse embryo communicate with each other and influence each others fate. Focus is on communication mediated by bone morphogenetic proteins (BMPs) in i) plasticity and reprogramming, and ii) blood vessel development; processes highly relevant for understanding tumor biology.
We make use of different unique genetic mouse tools (conventional and conditional Bmp-Smad mouse knockouts and reporter mouse; explant cultures and primary cells derived of these models) to address specific research questions.

Plasticity and reprogramming
In recent years, exciting progress has been made in the in vitro reprogramming of somatic cells from an adult mouse or human into more primitive, pluripotent cells with embryonic stem (ES)-like features. These cells which are called Induced pluripotent stem (iPS) cells, have therapeutical potential. However, the methods to reprogram cells are not fully understood, and emerging evidence suggests that iPS cells are prone to defects of reprogramming. Therefore novel approaches of reprogramming are still eagerly awaited. Our research has revealed that the amnion is a highly plastic tissue. In mouse, the amnion is a bilayered, avascular extra-embryonic membrane that envelops and protects the embryo in utero. We documented that cellular reprogramming occurs spontaneously in amnion of a mouse model that is deficient of Smad5, a Bmp intracellular signal mediator. In Smad5 mutants the amnion thickens locally and it undergoes ectopic vasculogenesis, haematopoiesis and in situ development of primordial germ cell (PGC)-like cells/stem cells; as if the mutant amnion develops a kind of a tumor. We aim to decode the basic principles of lineage switching from a population of apparently uniform amnion cells to more naïve stem cells/progenitor cells (reprogramming), and the subsequent differentiation to amongst others haematopoietic, endothelial and PGC-like cells when canonical Bmp signaling is impaired. The emerging picture seems that Smad5 mediated signalling is pivotal for amnion homeostasis, and that its deficiency in the amnion results in an ectopic signaling center that alters the fate of the amnion, and resets it to a more naive progenitor state.

One day, this type of research could be useful to guide terminally differentiated (patient) cells better to more primitive undifferentiated cells that then can be used to be reprogrammed to a desired cell type suitable for cell therapy.

Canonical Bmp signaling in blood vessel development
Embryonic blood vessel formation is a highly precise and reproducible process, that is guided by multiple signalling pathways. Morphogens of the vascular endothelial growth factors (VEGFs) and angiopoietins, and their receptor tyrosine kinases, are essential to give rise to a vascular network. Endothelial cell specification (tip cell vs. stalk cell; arterial, venous and lymphatic endothelial cells) is dependent amongst others on e.g. Notch receptor and its ligands. Bmps have recently been implicated in the development and maintenance of the vascular systems, but its precise role in early blood vessel formation and specification is incompletely understood. In our team, we investigate the in vivo role of the canonical Bmp signaling cascade in endothelial cells (EC) and smooth muscle cells (SMC) or pericytes, making use of several genetically modified mouse models.

This type of research gives insight into the genetic and molecular mechanisms that steer blood vessel formation and identity in physiological and/or pathological conditions, which may ultimately open avenues to potential therapeutic applications.

Umans L, Cox L, Tjwa M, Bito V, Vermeire L, Laperre K, Sipido K, Moons L, Huylebroeck D, Zwijsen A
Inactivation of Smad5 in Endothelial Cells and Smooth Muscle Cells Demonstrates that Smad5 Is Required for Cardiac Homeostasis
AM J PATHOL 170, 1460-72, 2007



Bosman E, Lawson K, Debruyn J, Beek L, Francis A, Schoonjans L, Huylebroeck D, Zwijsen A
Smad5 determines murine amnion fate through the control of bone morphogenetic protein expression and signalling levels
DEVELOPMENT 133, 3399-409, 2006

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