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A strength in the Dresden research landscape is the developmental cell biology of neural stem cells and neurodegenerative diseases. At the CRTD, we focus on the elucidation of mechanisms controlling neurogenesis – the proliferation and differentiation of neural stem cells – and apply this knowledge to the development of therapies to prevent cognitive decline. Utilizing the major regenerative and non-regenerative organisms, including drosophila, zebrafish, axolotl, mouse and human, the CRTD aims to define cell intrinsic and extrinsic factors that impact on productive neurogenesis during homeostasis and disease.

Models of Neural Plasticity

Regeneration of the zebrafish brain. Radial glial cells (green) in the periphery of the brain are neuronal precursors that move to the site of injury (blue) and give rise to new neurons (yellow). Over time complete neuroregeneration is achieved.

A fundamental problem in neurobiology is how the multitude of different cells of the brain is generated from their precursors, or stem cells. Prof. Michael Brand's group studies regeneration of the brain in zebrafish, which have a spectacular ability to regenerate and provide an ideal genetically and experimentally tractable system for understanding brain repair processes. The group has developed new methods for lesioning and manipulating the regenerating brain and retina, such as transgenic strains, Cre-loxP technology and FACS sorting of stem cell populations.

The Brand group demonstrated the key involvement of the Fgf pathway in controlling proliferation of adult neural stem cells in the brain (Kaslin et al., 2009; Ganz et al., 2010). Their approach using transgenic lines expressing fluorescent reporters in specific progenitor populations with subsequent FACS sorting allowed detection of genome-wide responses to lesion during regeneration of the CNS, and provided a host of new potential target genes and pathways (Kizil et al., 2012; Kyritsis et al., 2012).

A key achievement by the group of Prof. Gerd Kempermann is the finding that when both genes and environment are unchanged, individuality emerges and longitudinal behavioural trajectories are correlated with individual levels of brain plasticity and adult hippocampal neurogenesis (Freund et al., 2013) and in related studies, different mouse strains showed hugely different responses in the activity-dependent regulation of adult neurogenesis, e.g. after physical activity (Overall et al., 2013).

Dr. Jared Sterneckert's group generated isogenic iPSCs from patients with mutant LRRK2-induced Parkinson's disease (PD) (Reinhardt et al., 2013) and showed that mutant LRRK2 causes aberrant ERK phosphorylation, resulting in gene dysregulation and neurodegeneration. Furthermore, the group identified a novel type of iPSC-derived neuroepithelial stem cell that can be directed to self-renew in an immortal fashion using only small molecules, which enables automation of the iPSC-based PD model for drug discovery. Sterneckert's group demonstrated proof-of-principle for stem cell-based phenotypic screening using a model of amyotrophic lateral sclerosis (ALS), which identified neuroprotective compounds acting through multiple mechanisms (Hoing et al., 2012). Using its iPSC-based disease models, the group aims to identify neuroprotective compounds to treat patients with early-stage PD and/or ALS.

Prof. Federico Calegari's group has extended findings on the importance of the length of the cell cycle G1 phase in stem cell differentiation (Artegiani et al., 2011). The model implies that the duration of G1 is a limiting factor for the switch from a proliferative to a differentiation status and the Calegari group were able to switch the status of stem cells by manipulating cell cycle length. The model has also been validated in somatic stem cells beyond the central nervous system. The group is also exploring the role of long non-coding RNAs in the control of neurogenesis (Aprea et al., 2013).

The group of Prof. Elly Tanaka showed that spinal cord regeneration in the axolotl is implemented by a multipotent neural stem cell and that neural stem cells revert to an embryonic-like neuroepithelial state that is competent to elongate the body axis and undergo self-renewing divisions to grow a new spinal cord, which undergoes patterning in the adult (Fei et al., 2014). Based on this finding, they engineered a patterned neural tube organoid from mouse embryonic stem cells as a potential transplantable source for spinal cord injury (Meinhardt et al., 2014). The Tanaka lab is investigating how mouse spinal cord organoids are self-patterned by the global addition of retinoic acid.

Dr. Michell Reimer was the first to describe motor neuron regeneration from progenitor cells in the adult zebrafish spinal cord and how a long-range, brain-derived dopamine signal controls the extent of regeneration (Reimer et al., 2013). He helped identify and therapeutically target novel molecular pathways underlying the childhood motor neuron disease, spinal muscular atrophy (SMA) (Wishart et al., 2014). The Reimer lab is analyzing how remyelination after CNS injury is regulated and how to harness the regenerative capacity of oligodendroglia to improve functional outcome after CNS damage, like spinal cord injury.

Dr. Caghan Kizil's group is generating conditional transgenic models of neurodegeneration in adult zebrafish brain. Their work has been informative in elucidation of how regeneration could be made possible in some vertebrates using injury induced molecular programs. Kizil has identified gata3 as a key gene underlying regenerative response in adult neural stem cells of zebrafish brain (Kizil et al., 2012). The group is analyzing the molecular mechanisms that make adult stem cells responsive to chronic neuronal death in zebrafish. The Kizil group is working to model neurodegenerative diseases in zebrafish brain, where neural stem cells can regenerate neurons upon tissue loss.

References
  • Aprea J, Prenninger S, Dori M, Ghosh T, Monasor LS, Wessendorf E, Zocher S, Massalini S, Alexopoulou D, Lesche M, et al. (2013). Transcriptome sequencing during mouse brain development identifies long non-coding RNAs functionally involved in neurogenic commitment. EMBO J 32:3145-3160.
  • Artegiani B, Lindemann D, and Calegari F. (2011). Overexpression of cdk4 and cyclinD1 triggers greater expansion of neural stem cells in the adult mouse brain. J Exp Med. 208:937-948.
  • Fei JF, Schuez M, Tazaki A, Taniguchi Y, Roensch K, and Tanaka EM. (2014). CRISPR-mediated genomic deletion of Sox2 in the axolotl shows a requirement in spinal cord neural stem cell amplification during tail regeneration. Stem Cell Reports 3:444-459.
  • Freund J, Brandmaier AM, Lewejohann L, Kirste I, Kritzler M, Kruger A, Sachser N, Lindenberger U, and Kempermann G. (2013). Emergence of individuality in genetically identical mice. Science 340:756-759.
  • Ganz J, Kaslin J, Hochmann S, Freudenreich D, and Brand, M. (2010). Heterogeneity and Fgf dependence of adult neural progenitors in the zebrafish telencephalon. Glia 58:1345-1363.
  • Hochmann S, Kaslin J, Hans S, Weber A, Machate A, Geffarth M, Funk RH, and Brand, M. (2012). Fgf signaling is required for photoreceptor maintenance in the adult zebrafish retina. PloS One 7:e30365.
  • Hoing S, Rudhard Y, Reinhardt P, Glatza M, Stehling M, Wu G, Peiker C, Bocker A, Parga JA, Bunk E, et al. (2012). Discovery of inhibitors of microglial neurotoxicity acting through multiple mechanisms using a stem-cell-based phenotypic assay. Cell Stem Cell 11:620-632.
  • 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 29:6142-6153.
  • Kizil C, Kyritsis N, Dudczig S, Kroehne V, Freudenreich D, Kaslin J, and Brand M. (2012). Regenerative neurogenesis from neural progenitor cells requires injury-induced expression of Gata3. Developmental Cell 23:1230-1237.
  • Kyritsis N, Kizil C, and Brand M. (2014). Neuroinflammation and central nervous system regeneration in vertebrates. Trends Cell Biology 24:128-135.
  • Meinhardt A, Eberle D, Tazaki A, Ranga A, Niesche M, Wilsch-Brauninger M, Stec A, Schackert G, Lutolf M, and Tanaka EM. (2014). 3D Reconstitution of the Patterned Neural Tube from Embryonic Stem Cells. Stem Cell Reports 3:987-999.
  • Overall RW, Walker TL, Leiter O, Lenke S, Ruhwald S, and Kempermann G. (2013). Delayed and transient increase of adult hippocampal neurogenesis by physical exercise in DBA/2 mice. PloS One 8:e83797.
  • Reimer MM, Norris A, Ohnmacht J, Patani R, Zhong Z, Dias TB, Kuscha V, Scott AL, Chen YC, Rozov S, et al. (2013). Dopamine from the brain promotes spinal motor neuron generation during development and adult regeneration. Developmental Cell 25:478-491.
  • Reinhardt P, Schmid B, Burbulla LF, Schondorf DC, Wagner L, Glatza M, Hoing S, Hargus G, Heck SA, Dhingra A, et al. (2013). Genetic correction of a LRRK2 mutation in human iPSCs links parkinsonian neurodegeneration to ERK-dependent changes in gene expression. Cell Stem Cell 12:354-367.
  • Wishart TM, Mutsaers CA, Riessland M, Reimer MM, Hunter G, Hannam ML, Eaton SL, Fuller HR, Roche SL, Somers E, et al. (2014). Dysregulation of ubiquitin homeostasis and beta-catenin signaling promote spinal muscular atrophy. The J Clin Invest. 124:1821-1834.