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Roussa Group

Prof. Dr. med. dent. Eleni Roussa

Department of Molecular Embryology

Institute of Anatomy and Cell Biology

Albertstr. 17

79104 Freiburg

Tel: 0761 2035114

Lab: 0761 2035063

Email: eleni.roussa@anat.uni-freiburg.de

Website: Prof. Dr. Roussa

Current Research

Current projects include:

Regulation of H+ and HCO3- transport proteins in salivary glands in health and disease

Bicarbonate ions represent the main buffer in saliva. Bicarbonate is secreted into the saliva by the salivary duct cells, it plays a crucial role in limiting the pH change following acid production of plaque bacteria, and is active at the critical pH at which enamel begins to dissolve in saliva. However, the mechanisms underlying bicarbonate secretion and the regulation of the acid-base transporters involved are not fully elucidated.

In our lab we have been working on the molecular characterization of acid-base transporters involved in intracellular pH regulation and bicarbonate transport in salivary glands in health and disease. Our previous work has demonstrated expression of two transport proteins that have not been considered in the current models for water and electrolyte secretion by salivary glands, namely a vacuolar H+-ATPase and an electrogenic Na+/HCO3- cotransporter (NBCe1). We have also shown that adaptive redistribution of the vacuolar H+-ATPase and of the NH2-terminal variants of the electrogenic Na+/HCO3- cotransporter 1 (NBCe1-A and NBCe1-B) in salivary ducts is a potent regulatory mechanism as response to systemic acid-base disturbances.

We are currently focusing on the identification of molecular and functional mechanisms accountable for regulation of the identified H+ and HCO3- transporters in duct cells of salivary glands under physiological conditions and in response to acid or alkali load. We want to understand the biological significance of transporter traffic in intracellular pH regulation and bicarbonate transport, as well as the molecular basis of transporter redistribution. Thereby we will develop a better understanding of fundamental processes during intracellular pH regulation, bicarbonate secretion and final electrolyte composition of the saliva, as well as regulation of acid-base transporters in health and disease.

Publications:

Brandes A, Oehlke O, Schümann A, Heidrich S, Thévenod F, Roussa E (2008) Differential regulation of SLC4A4 splice variants, NBCe1-A and NBCe1-B, in striated ducts of rat salivary glands and renal proximal tubule during acid-base disturbances. Am J Physiol Regul Integr Comp Physiol 293:R2400-2411.

Rickmann M, Orlowski B, Heupel K, Roussa E (2007) Distinct expression and subcellular localization patterns of Na+/HCO3- cotransporter (SLC4A4) variants NBCe1-A and NBCe1-B in mouse brain. Neuroscience 146:1220-1231.

Oehlke O, Sprysch P, Rickmann M, Roussa E (2006) Na+/H+ exchanger isoforms are differentially regulated in rat submandibular gland during acid/base disturbances in vivo. Cell Tissue Res 323:253-262.

Roussa E, Nastainczyk W, Thévenod F (2004) Differential expression of electrogenic NBC1 (SLC4A4) variants in rat kidney and pancreas. Biochem Biophys Res Commun 14:382-389

Thévenod F, Roussa E, Schmitt BM, Romero MF (1999) Cloning and immunolocalization of a rat pancreatic Na+ Bicarbonate Cotransporter. Biochemical and Biophysical research Communications 264:291-298.

Roussa E, Romero MF, Schmitt BM, Boron WF, Alper SL, Thévenod F (1999) Immunolocalization of anion exchanger AE2 and Na+/HCO3- cotransporter (NBC) in rat parotid and submandibular glands. American Journal of Physiology 277,G1288-G1296.

Roussa E, Alper SL, Thévenod F (2001) Immunolocalization of anionexchanger AE2, Na+/H+ exchangers NHE1 and NHE4, and vacuolar type H+-ATPase in rat pancreas. Journal of Histochemistry and Cytochemistry 49:463-474.

TGF-ß superfamily and tooth development

Tooth development is a dynamic process that is regulated by sequential and reciprocal interactions between dental epithelium, derived from oral ectoderm, and mesenchyme, a derivative of cranial neural crest. Tooth morphogenesis is dominated by the formation of the transient signaling center enamel knot whose signals provide positional information for tooth morphogenesis and regulate patterning and shape of the tooth crown. To date over 300 genes have been associated with the patterning and morphogenesis, as well as cell differentiation in teeth. It is meanwhile well established that cell communication during tooth development is mediated by the interaction between extrinsic and intrinsic determinants. Several diffusible signal molecules of conserved families, such members of the TGF-ß superfamily, have been identified as key extrinsic factors. Extrinsic factors may act as an autocrine or paracrine mode and regulate the spatial and temporal expression not only of other extrinsic molecules, but also of intrinsic determinants, by means of the transcriptional equipment of the epithelial and mesenchymal cells.

We are interested in understanding the biological significance of members of the TGF-ß supberfamily and their interactions in dental epethelium and underlying mesenchyme during the different stages of tooth development. Several mouse mutants and a broad spectrum of in virtro approaches serve as experimental models.

Development of serotonergic neurons

Cell and neuron subpopulations in the CNS differentiate in stereotypic, defined positions along the anterior-posterior and dorso-ventral axes of the neural tube and exhibit a cell-type-specific transcriptional code. Among ventral neuronal subpopulations, serotonergic (5-HT) neurons are of particular interest, because of their involvement in neurological diseases. Dysfunction of the serotonergic system is related with depression, obsessive-compulsive disorder, and schizophrenia. According to current knowledge of patterning of the CNS, cell fate decisions along the dorsoventral and anterior-posterior axis of the neural tube are dictated by diffusible signals from signaling and organizing centers. Rostral hindbrain 5HT neurons development depends on Shh, representing the inductive signal from the floor plate, FGF8, the corresponding signal from the midbrain-hindbrain-boundary, and FGF4. However, the mechanisms of serotonergic neuron development have not been unambiguously elucidated and recent studies have challenged the prevailing model for serotonergic neuron development. Specifically, the network of intrinsic and extrinsic regional determinants that dictate differentiation of progenitor cells toward serotonergic neurons is far from being complete and additional/alternative molecules emerge as potent candidates.

In order to complete this network and identify new candidate genes, we have established a primary neurospheres culture system from mouse ventral rostral hindbrain embryonic day (E) 12. This in vitro model system exhibits the main characteristics of progenitor cells: a) the ability to proliferate and b) the capacity of multilineage differentiation. Hereby it allows the enrichment of progenitor cells, and also triggers these cells towards a specific cell fate. This cellular approach is complemented in vivo by generating mouse mutants and performing phenotype analysis.

The results will provide cues for a better understanding of specification of neuronal fate and neurotransmitter phenotype.

Publications:

Osterberg, N., Roussa, E., (2009) Characterization of primary neurospheres generated from mouse ventral rostral hindbrain. Cell Tissue Res. 336: 11-20.

Roussa, E., Oehlke, O., Rahhal, B., Heermann S., Heidrich, S., Wiehle M., Krieglstein, K. (2008) TGFß co-operates with Persephin for dopaminergic phenotype induction. Stem Cells; 26: 1683-1694.

Roussa, E., Wiehle M., Dünker N, Becker-Katins S., Oehlke O., Krieglstein, K., (2006) TGF-ß is required for differentiation of mouse mesencephalic progenitors into dopaminergic neurons in vitro and in vivo. Ectopic induction in dorsal mesencephalon. Stem cells 24: 2120-2129.

Roussa, E., Farkas L., Krieglstein, K. (2004) TGF-beta promotes survival on mesencephalic dopaminergic neurons in cooperation with Shh and FGF-8. Neurobiol Dis 16:300-310.

Roussa, E., Krieglstein, K. (2004) GDNF promotes neuronal differentiation and dopaminergic development of mouse mesencephalic neurospheres. Neuroscie Let 361:52-55.

Roussa E., Krieglstein, K., (2004) Induction and specification of dopaminergic cells development: focus on TGF-ß, Shh and FGF8. Cell Tissue Res 318: 23-33.

Group members

Frau Enaam Chleilat

Herr Fabian Cardenas Lara

Frau Shokoufeh Khakipoor

Frau Melanie Feuerstein

Frau Manal Hussein

Frau Magdalena Schrödl