Cellular and Molecular Biology of Thalamus Development
Final Report Abstract
The number of patients suffering of neurodegenerative diseases is rapidly increasing in the last 30 years and in many of these patients the thalamus is affected. So far a satisfying treatment is lacking. We want to understand the developmental program of the thalamic complex to establish the basis for a future therapeutically approach – either by activating quiescent stem cells in-vivo or engineering a cell culture system to develop this complex brain part in-vitro. Therefore, we use the zebrafish as a model organism to elucidate signaling process and transcription factor cascades acting during diencephalon development. We complement our analysis by developing advanced cell culture systems to analyze these processes in a controlled environment. We were able to elucidate novel aspects in thalamus development. The mid-diencepahlic organizer (MDO) orchestrates the development of the thalamus. We provided evidence that Shh signaling - emitted from the organizer population - regulates neuronal differentiation in the diencephalon. We showed that Wnt signaling is required for formation of the MDO. In parallel, Wnt signaling is required to regulate compartmentalization in the diencephalon. Wnt signaling regulates the expression of Pcdh10b, which modulates cell adhesion in the thalamus. Furthermore, we analyzed the function of the transcription factors Lhx2, Lhx9 and Pax6. We showed that these factors are needed for thalamic neurogenesis. In addition to Lhx2/Lhx9, Wnt signaling seems to be also required during neurogenesis. Furthermore, Pax6 restricts the MDO and thus influences the effect of long-range Shh signaling on more distant brain parts, such as the epithalamus. In parallel, we studied the formation of the Wnt signaling gradient. We have identified one subunit of the endocytic Ap2 complex, Ap2µ2, which is ubiquitously expressed and enriched in neuronal populations such as the thalamus. We provide evidence that Ap2µ2 affects the Wnt/β- Catenin signaling cascade. Ap2µ2 is a direct binding partner of the Wnt effector Dvl. We found that Ap2µ2 is important for stabilization of Dvl at the membrane. By an 4D in-vivo imaging approach, we found that Ap2µ2-dependent endocytosis is a prerequisite for the activation of the Wnt/β-Catenin signaling cascade. In addition, we established 2D / 3D cell culture systems to guide cells and to control signaling. We will use these systems to differentiate pluripotent neuroepithelium cells into diseased neural structures by exposing them sequentially to our identified external cues. In summary, we discovered novel genetic interactions during thalamus development and we developed novel tools for 3D cell cultivation. Theses are important steps towards a future cell replacement strategy.
Publications
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Her6 regulates the neurogenetic gradient and neuronal identity in the thalamus. PNAS 2009. Nov 24;106(47):19895-900
Scholpp, S., Delogu, A., Gilthorpe, J. Peuckert, D., Schindler, S., and Lumsden A.
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Lhx2 and Lhx9 determine neuronal differentiation and compartition in the caudal forebrain by regulating Wnt signalling. PLoS Biology 2011 Dec 13: 9(12): e1001218
Peukert, D., Weber, S., Lumsden, A. and Scholpp, S.
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Wnt3 and Wnt3a are required for induction of the mid-diencephalic organizer in the caudal forebrain. Neural Development 2012 Apr; 7, 12
Mattes, Benjamin; Weber, Sabrina; Peres, João; Chen, Qing; Davidson, Gary; Houart, Corinne & Scholpp, Steffen
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A facile technique for studying compartition and interaction of multiple cell populations in vitro. Biomaterials. 2013 Feb;34(7):1757-63
Efremov, A., Stanganello, E., Welle, A., Scholpp, S. and Levkin P.
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Endocytosis of Fgf8 is a double-stage process and regulates spreading and signalling. PLoS One. 2014 Jan 20;9(1):e86373
Rengarajan, Charanya; Matzke, Alexandra; Reiner, Luisa; Orian-Rousseau, Véronique & Scholpp, Steffen
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In-vivo analysis of formation and endocytosis of the Wnt/β-Catenin receptor signaling complex in zebrafish J. Cell Science., 2014 Sep 15;127(Pt 18):3970-82
Hagemann, Anja I. H.; Kurz, Jennifer; Kauffeld, Silke; Chen, Qing; Reeves, Patrick M.; Weber, Sabrina; Schindler, Simone; Davidson, Gary; Kirchhausen, Tomas & Scholpp, Steffen
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Pax6 regulates the formation of the habenular nuclei by controlling the temporospatial expression of Shh in the diencephalon in vertebrates. BMC Biology 2014 Feb 14;12:13
Chatterjee, Mallika; Guo, Qiuxia; Weber, Sabrina; Scholpp, Steffen & Li, James YH
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Tyrosine phosphorylation of LRP6 by Src and Fer inhibits Wnt/ß-Catenin signalling. EMBO Reports, 2014 Dec;15(12):1254-67
Chen, Qing; Su, Yi; Wesslowski, Janine; Hagemann, Anja I; Ramialison, Mirana; Wittbrodt, Joachim; Scholpp, Steffen & Davidson, Gary
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Filopodia-based Wnt transport during vertebrate tissue patterning. Nature Communications, 2015 Jan;5(6):5846
Stanganello, Eliana; Hagemann, Anja I. H.; Mattes, Benjamin; Sinner, Claude; Meyen, Dana; Weber, Sabrina; Schug, Alexander; Raz, Erez & Scholpp, Steffen
