BIOTEC - Biotechnology Center TU Dresden

A fundamental problem in neurobiology is how the multitude of different cells and their connections are generated from their precursors, or stem cells. We have studied extensively how embryonic neural precursor cells at the border between midbrain and hindbrain (MHB) act as organizers of cell fate onto the surrounding cells, which eventually form the midbrain and cerebellum. We also study which signals determine where the MHB organizer forms initially. Fgf8 is absolutely required for MHB organizing activity. For instance, zebrafish acerebellar mutants have no functional Fgf8, and hence lack a cerebellum and proper polarity in the midbrain. In genetic, cell biological and biophysical studies, we are unraveling how secreted Fgf signals exert their function at the MHB and in other embryonic organizer cell populations.

More recently we have probed for a possible role of organizer- associated signaling molecules also in the adult brain. We find that in contrast to mammals, adult zebrafish brains retain an amazing number of active neural stem cells at all times, and in very discreet spatial domains. Given the well known ability of teleost brains to repair damage, and the lack thereof in mammalian brains, stem cell based regeneration studies in fish may provide clues which mechanisms need to be activated to stimulate CNS regeneration also in mammalian brains. Indeed numerous new neurons of different subtypes are produced in the adult zebrafish brain, providing an ideal genetically and experimentally tracktable system for understanding brain repair processes.

• organizer-dependent patterning and differention processes in the embryonic and adult vertebrate brain
• understanding stem cell activity and control in the adult CNS of a regenerating vertebrate

2009
Picker A, Cavodeassi F, Machate A, Bernauer S, Hans S, Abe G, Kawakami K, Wilson SW, Brand M. (2009) Dynamic coupling of pattern formation and morphogenesis in the developing vertebrate retina. PLoS Biol. Epub 2009 Oct 13.

Yu, S.R., Burkhardt, M., Nowak, M., Ries, J., Petrášek, Z., Scholpp, S., Schwille, P. and Brand, M. (2009). FGF8 morphogen gradient is formed by a source-sink mechanism with freely-diffusing molecules. Nature, Sep 24;461(7263):533-6

Ries, J. , Yu, S. R., Burkhardt, M., Brand, M. and Schwille, P. (2009). Modular scanning FCS quantifies ligand-receptor interactions in live multicellular organisms. Nature Methods, Aug 2. PMID: 19648917.

Rhinn M, Lun K, Ahrendt R, Geffarth M, Brand M. (2009) Zebrafish gbx1 refines the midbrain-hindbrain boundary border and mediates the Wnt8 posteriorization signal. Neural Dev. 2009 Apr 2;4:12.

Kaslin, J., Ganz, J., Geffarth, M., Grandel, H., Hans, S. and Brand M. (2009). Stem Cells in the Adult Zebrafish Cerebellum: Initiation and Maintenance of a Novel Stem Cell Niche. J Neuroscience, May 13;29(19):6142-53. PMID: 19439592 [PubMed - in process]

Picker A, Roellig D, Pourquié O, Oates AC, Brand M. (2009) Tissue micromanipulation in zebrafish embryos. Methods Mol Biol. 546:153-72.

Hans, S., Kaslin, J., Freudenreich, D., and Brand, M. (2009). Temporally-controlled Site-specific Recombination in Zebrafish. PLoS ONE. 2009;4(2):e4640. Epub 2009 Feb 27.

2008
Schenck, A., Goto-Silva, L., Collinet, C., Rhinn, M., Giner, A., Habermann, B., Brand, M. and Zerial, M. (2008). The endosomal protein APPL1 mediates Akt substrate specificity and cell survival in vertebrate development. Cell. 2008 May 2;133(3):399-400.

Kaslin J, Ganz J, Brand M. (2008). Proliferation, neurogenesis and regeneration in the non-mammalian vertebrate brain. Philos Trans R Soc Lond B Biol Sci. 29;363 (1489):101-122.

2007
Scholpp, S. and Brand, M. (2007) Regionalisation of the neural tube: a balance between organizers and competence fields. New Encyclopedia for Neuroscience 2007, Ed. Larry Squire, UCSD School of Medicine, USA.

Wendl T, Adzic D, Schoenebeck JJ, Scholpp S, Brand M, Yelon D, Rohr KB. (2007). Early developmental specification of the thyroid gland depends on han-expressing surrounding tissue and on FGF signals. Development 134(15):2871-2879.

Erickson, T., Scholpp, S., Brand, M., Moens, C. B., and Waskiewicz, A. J. (2007). Pbx proteins cooperate with Engrailed to pattern the diencephalon-midbrain boundary. Developmental Biology 301, 504-517.

Funfak, A. Brösing, A., Brand, M. and Köhler, J.M. (2007). Micro-fluid segment technique for screening and development studies on Danio rerio embryos. Royal Soc Chemistry LOC, 7(9):1132-1138.

Erickson, T., Scholpp, S., Brand, M., Moens, C. B., and Waskiewicz, A. J. (2007). Pbx proteins cooperate with Engrailed to pattern the diencephalon-midbrain boundary. Developmental Biology, Jan 15;301(2):504-17. doi: 10.1016/j.ydbio.2006.08.022

2006
Grandel, H., Kaslin, J., Ganz, J., Wenzel, I., and Brand, M. (2006). Neural stem cells and neurogenesis in the adult zebrafish brain: origin, proliferation dynamics, migration and cell fate. Developmental Biology, 295(1):263-277.

Reim, G., and Brand, M. (2006). Maternal control of vertebrate dorso-ventral axis formation and epiboly by the POU domain protein Spg/Pou2/Oct4. Development, 133(14):2757-2770.

Scholpp, S., Wolff, O. , Brand, M. and Lumsden, A. (2006). Hedgehog signalling from the Zona Limitans Intrathalamica orchestrates differentiation of the zebrafish diencephalon. Development 133, 855-864.

Rhinn, M., Picker, A., and Brand, M. (2006). Global and local mechanisms of forebrain and midbrain patterning. Curr Opin Neurobiology 16, 1-8.

Langenberg, T., Dracz, T., Oates, A.C., Heisenberg, C.P. and Brand, M. (2006): Analysis and visualization of cell movement in the developing zebrafish brain. Developmental Dynamics, 235(4); 928-933.

Scholpp, S. and Brand, M. (2006) Regionalisation of the neural tube: a balance between organizers and competence fields. New Encyclopedia for Neuroscience 2007, Ed. Larry Squire, UCSD School of Medicine, USA. Submitted.

2005
Picker, A. and Brand, M. (2005): Fgf-signals from a novel signaling center determine axial patterning of the prospective neural retina. Development 132 (22):4951-4962

Rhinn, M., Lun, K., Luz, M., Werner, M., Brand, M. (2005). Positioning of the midbrain-hindbrain boundary organizer through global posteriorisation of the neuroectoderm mediated by Wnt8 signaling. Development 132, 1261-1272.

Winkler, S., Schwabedissen, A., Backasch, D., Bökel, C., Seidel, C., Bönisch, S., Fürthauer, M., Kuhrs, A., Cobreros, L, Brand, M. and González-Gaitán, M. (2005). Target-selected mutant screen by TILLING in Drosophila. Genome Research, 15(5):718-723.

Langenberg, T.L. and Brand, M. (2005). Lineage restriction maintains a stable organizer cell population at the zebrafish midbrain-hindbrain boundary. Development, 132(14):3209-3216.

Neural Stem Cell Activity During Adult Neurogenesis and Regeneration
A key process that is controlled by embryonic organizers like the MHB, and that is thought to be deficient in aging or diseased brains, is the proliferation of the progenitor or stem cells that give rise to the cell types in the brain. Mammalian brains differ from brains of many other vertebrates, including zebrafish, in one important aspect: Whereas in mammalian brains new neurons are born only in very restricted areas, zebrafish brains continuously produce new brain cells throughout. Our goal is therefore to understand the mechanisms that allow neural stem cells to remain active in zebrafish brains, in order to better understand how we might reactivate stem cell activity also in aging and diseased mammalian brains.
For further information, see also the Center for Regenerative Therapies (CRTD) and the Sonderforschungsbereich Cells into Tissues (SFB 655).

Genetic analysis of MHB development
A pivotal approach in our work is to manipulate the cascade of genes that regulate MHB development and function. After having intensively studied central genetic determinants of the MHB like Fgf8, Pax2a and Pou2 through mutant analysis we are now focusing on a detailed understanding of the cellular signaling and tissue distribution mechanisms of molecules involved in MHB organizer development.

Wnt8 - Upstream of the MHB
Wnt8 is signaling molecule that is needed to position the MHB organizer along the anterior-posterior axis in the early neural plate. The gene is expressed in the blastoderm margin of the gastrula embryo. We have shown that positioning of the MHB organizer is tightly linked to overall neuroectodermal posteriorization, and specifically depends on Wnt8 signaling emanating from lateral mesendodermal precursors, through defining the interface between cells expressing the Otx and Gbx transcription factors. We are currently investigating the spatial and temporal details of the molecular events that lead to early anterior-posterior patterning and MHB positioning.

MHB-dependent Polarization of the Neural Tube
In zebrafish acerebellar (ace) embryos, because of a point mutation in the Fgf8 gene, the isthmic constriction containing the MHB organizer fails to form. The absence of an MHB causes non-autonomous polarity changes along the anterior-posterior axis of the neural tube, which are reflected in altered gene expression, cell proliferation and changes in topographic axon projections.

Cellular Mechanisms of Inductive Signal Propagation
Inductive tissue interactions during embryonic development can occur over a significant spatial range. In the course of inductive processes secreted signaling molecules, such as Fgfs, need to travel from a defined source through the complex lattice of the extracellular matrix to responding target cells. It is our aim to gain a quantitative understanding on how signals spread in the embryo and are processed by responsive cells through using biochemical and biophysical approaches and advanced microscopic imaging.

Cellular Movements and Fates at the MHB
The vertebrate hindbrain is subdivided into segments, termed neuromeres, that are units of gene expression, cell differentiation and behavior. A key property of such segments is that cells show a restricted ability to mix across segment borders, termed lineage restriction. In order to address segmentation and lineage restriction in the MHB region, we have analyzed single cell behavior in the living embryo and find that midbrain and hindbrain cells arise from two distinct cell populations. Our findings suggest that segmentation as an organizing principle in early brain development can be extended to the MHB region. Ongoing work is aiming at the cellular and molecular mechanisms that underlie lineage restriction at the MHB.

Fgf-signaling During Ear Development
The vertebrate inner ear develops from initially 'simple' ectodermal placode and vesicle stages into the complex three-dimensional structure, which is necessary for the senses of hearing and equilibrium. We have studied the role of combined Fgf signaling during placode induction, maintenance and otic vesicle patterning.

DFG-Center for Regenerative Therapies Dresden (CRTD)  

SFB 655

Tracepilot - TracePilot and BioImage WIP are open-source software solutions that simplify the analyzes of phenotypes related to cell motility.

Lecture Materials for students

All current group members are listed on the Staff Page.