Chemical biology, haematopoietic and neural cell differentiation, signalling pathways, nuclear receptors, zebrafish

The main interest of the laboratory is study of the molecular mechanism of cell fate determination. We have established in vitro systems to get insight into the self-renewal and diff erentiation of haematopoietic, neural and mesenchymal stem cells. We use growth factors and small molecules as tools to manipulate these systems. More recently, we have initiated a more systematic search for such tools using chemical biology approaches.

Recently, we have identifi ed Disp3, a sterol-sensing domain-containing protein. DISP3 (PTCHD2) is predominantly expressed in neural tissues. Ectopic expression of DISP3 in fi broblasts resulted in elevated cholesterol levels combined with an altered cholesterol and lipid distribution (Zikova et al. 2009). We have performed RNAi and overexpression studies of neural stem cell lines and found out that Disp3 is able to modulate the cell fate of neural stem and progenitor cells. We found that ectopically expressed DISP3 promotes cell proliferation and alters expression of genes that are involved in tumorigenesis. Finally, the diff erentiation profi le of DISP3-expressing cells was altered, as evidenced by delayed expression of neural specifi c markers and a reduced capacity to undergo neuraldifferentiation (Zikova et al. 2014).

We have extended our studies on vertebrate haematopoietic development to the zebrafi sh model and we have established ex vivo cultures of haematopoietic cells (Stachura et al. 2009). Recently, we have produced several recombinant zebrafi sh growth factors (Epo, Gcsfa/b, Tpo) that allow us to establish, for the fi rst time, zebrafi sh haematopoietic clonal assays in semisolid media (Stachura et al. 2011). Granulocyte colony-stimulating factor (Gcsf) drives the proliferation and diff erentiation of granulocytes, monocytes, and macrophages. Analysis of the zebrafi sh genome indicates the presence of two Gcsfs, likely resulting from a duplication event in teleost evolution. We show that in addition to supporting myeloid diff erentiation, zebrafi sh Gcsf is required for the specifi cation and proliferation of haematopoietic stem and progenitor cells. These fi ndings may bring information on how haematopoietic cytokines had evolved following the diversifi cation of teleosts and mammals from a common ancestor (Stachura et al. 2013). Moreover, these tools enabled us to reveal the clonogenic and proliferation capacity of bi-potent thrombo/erythropoietic progenitors with respect to their mammalian haematopoietic counterparts. Despite obvious phenotypic diff erences between fi sh and mammalian thrombocytes and erythrocytes, our results strongly demonstrate the evolutionary conservation of the basic processes and molecular mechanisms of erythro/thrombopoiesis in the vertebrates (Svoboda et al. 2014).

Last change: March 8, 2016