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Unsicker Group

Prof. Dr. Klaus Unsicker

Department of Molecular Embryology

Institute of Anatomy and Cell Biology

Albertstr. 17

79104 Freiburg

 

Tel: 0761 / 203 5193

Email: ku39@anat.uni-freiburg.de

Website: Prof. Dr. Klaus Unsicker

 

 

 

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Growth factors in development and functions of the nervous system

 

 

 

Current Research

 

The Unsicker lab studies aspects of neural development, functions, and disease, addressing both molecular-cellular and systems issues. We focus on the development of neural crest (NC) derivatives, functions of limbic areas, and meso-striatal / meso-limibic systems in health and disease. We have a long-standing interest in the roles of select members of the transforming growth factor-ßs (TGF-ßs), fibroblast growth factors (FGFs), and neurotrophins.

An important topic in the research of the laboratory is the molecular understanding of neuronal survival and death. Methodologies include generation and analysis of mouse mutants, cell and tissue culture, biochemistry, molecular biology, histology, and electrophysiology. Several projects of the group are described below.

 

Current projects include

Generation of cell diversity in the sympathoadrenal (SA) cell lineage of the NC

Functions of Growth Differentiation Factor-15 (GDF-15)

Requirement of neurotrophin signalling for the maintenance of dendritic spines

and the midbrain dopaminergic system

Functions of fibroblast growth factors (FGFs) in neuron generation, maintenance

and astroglia differentiation

 

Generation of cell diversity in the sympathoadrenal (SA) cell lineage of the NC

 

The NC gives rise to different types of neurons, glial, endocrine, and mesenchymal cells and, hence, is an excellent model for exploring mechanisms underlying the generation of cell diversity. We focus on the development of sympathetic neurons and neuroendocrine chromaffin cells. Whether these cells are derived from one common lineage, the SA cell lineage, or from two distinct lineages has been an open issue until very recently. In a joint effort with the Kalcheim lab (Hebrew University Jerusalem) we have performed single cell electroporations of GFP-encoding plasmid into delaminating NC cells in chick embryos and followed their subsequent migration into the target organs, i.e. sympathetic ganglia and adrenal gland, respectively. In the large majority of cases the progeny of GFP-expressing cells was detected in both sympathetic ganglia and adrenal glands suggesting that the cells share a common progenitor at the level of the neural tube [1]. In previous studies we have shown that, contrary to a classic hypothesis, glucocorticoid hormones and the adrenal cortex are not required for most aspects of chromaffin cell differentiation [2,3]. Furthermore, we have analyzed, inter alia, the transcription factor network underlying chromaffin cell development [e.g. 4,8] and the role of BMP-4 for chromaffin cell fate determination and differentiation [5; cf. figure].

Furthermore, in a collaboration with the Schütz lab (DKFZ Heidelberg) we study the role of glucocorticoids for the maintenance of intra- and extra-adrenal chromaffin tissue [6,7] and the impact of autophagy on chromaffin cell survival. For a recent review, see [8]. Current experiments, conducted in a collaboration with the Ernsberger, Rohrer (MPI Frankfurt) and Huber (Anatomy Freiburg) labs elucidate the role of microRNAs for sympathetic neuron and chromaffin cell development [9]. Our final goal is to fully understand the mechanisms that generate the diversity of sympathetic neurons and chromaffin cells during migration of progenitors to the target regions.

 

Bild2 Forschung Unsicker

E15 embryonic chick adrenal gland showing expression of BMP-4 mRNA (blue) and TH mRNA.

 

Selected Publications

 

[1] Shtukmaster, S. et al. (2013) Neural Development 8:12 doi:10:1186/1749-8104-8-12

[2] Finotto, S. et al. (1999) Development 126, 2935-2944

[3] Gut, P. et al. (2005) Development 132, 4611-4619

[4] Huber, K. et al.. (2002) Development 129, 4729-4738

[5] Huber, K. et al. (2008) Neural Development 3, 28 doi :191186/1749-8104-3-28

[6] Parlato, R. et al. (2009) Endocrinology 150, 1775-1781

[7] Schober, A. et al. (2013) Neuroendocrinology 25, 34-47

[8] Unsicker, K. et al. (2013) Mech. Dev. 130: 324-329

[9] Stubbusch, J. et al. (2013) Neural Development 8: 16

[10] Stubbusch, J. et al. (2015) Dev. Biol. 400:210-233

 

Functions of Growth Differentiation Factor-15 (GDF-15)

 

GDF-15 is a novel distant member of the TGF-ßs, originally identified in our laboratory as a potent trophic factor for midbrain dopaminergic neurons, the neuron population predominantly affected in Parkinson's disease [1]. We have generated a GDF-15 knockout mouse, which shows progressive postnatal motoneuron loss and dysmyelination in peripheral nerves [2].

GDF-15 also seems to be involved in the generation and differentiation of neural stem cells. (in collaboration with the Ciccolini lab, IZN Heidelberg, and the von Bohlen lab, Greifswald). Despite its potency as a neurotrophic factor, when applied to CNS [1] and PNS lesion paradigms [3], analysis of GDF-15 knockout mice has revealed that endogenous GDF-15 implies no benefit to CNS neurons following lesion [4,5]. For a recent review, see [6].

 

 

Selected Publications

 

[1] Strelau, J. et al. (2000) J. Neuroscience 20: 8597-8603

[2] Strelau, J. et al. (2009) J. Neuroscience 29: 13640-13648

[3] Carrillo-Garcia, C. et. al. (20149 Development 141.773-783

[4] Mensching, L. et al. (2012) Cell Tiss Res. 350: 225-238

[5] Charalambous, P. et al. (2013) Cell Tiss Res. 353: 1-8

[6] Wang, X. et al. (2015) Cell Tiss. Res. 362:317-330

[7] Machado, V. et al.(2016) Neurobiol. Dis. 88:1-15

[8] Unsicker, K. et al. (2013) Cytokine Growth Factor Rev. 24: 373-384

 

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New neurons in dentate gyrus labeled with doublecortin

 

Requirement of neurotrophin signalling for the maintenance of dendritic spines and the midbrain dopaminergic system

 

The neurotrophins (BDNF) and neurotrophin-3, as well as their receptors trkB and trkC, respectively, are widely expressed in the nervous system and serve important functions during development. In a collaboration with the von Bohlen lab, Greifswald, we have found that aged mice, which are heterozygous null for trkB and trkC, show pronounced losses of midbrain dopaminergic neurons, including accumulations of α-synuclein (red in figure below), a hallmark of Parkinson´s disease [1].

 

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Analyses of mice with partial or regionally specific complete deficits in trkB expression have revealed specific reductions and morphological alterations in dendritic spines (see figure below), essential structures in synaptic signalling and the determination of behaviour [2].

 

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In collaborations with the von Bohlen, Grass, and Hempstead laboratories we have revisited roles of the neurotrophin receptor p7 fo hippocampal structure and cholinergic system [cf. 3,4].

 

Selected Publications

 

[1] Bohlen und Halbach, O.v, et al. (2005) FASEB J. 19: 1740-1742

[2] Bohlen und Halbach, O.v., et al. (2006) Biol. Psychiatry 59: 793-800

[3] Egorov, A.V. et al. (2006) Eur. J. Neuroscience 24: 3183-3194

[4] Dokter, M. et al. (2015) Brain Struct. Funct. 220:1449-1462

[5] Poser, R. et al. (2015) Front. Neuroanat. 9:63

[6] Imrady, K. et al. (2014) j. Neuroscience 34:3419-3428

 

Functions of fibroblast growth factors (FGFs) in neuron generation, maintenance, and astroglia differentiation

 

The laboratory has made seminal contributions to elucidating functions of FGFs (with a focus on FGF-2) in the nervous system. These include, inter alia, promotion of survival of select developing and lesioned neuron populations in the central and peripheral nervous system [1,2]. Using FGF-2- and FGF receptor-deficient mice we study the physiological relevance of FGF signalling for midbrain dopaminergic and cortical neurons [4, 9], FGF-dependent regulation of astroglia differentiation [3, 5, 8], neural progenitor cells in the dentate gyrus [7],and the role of FGFs in animal models of major depression [6] (in collaborations with the von Bohlen lab, Greifswald, the Gass lab, ZI Mannheim, and the Ek and Saunders labs, Gothenburg, Melbourne).

 

Selected Publications

 

[1] Unsicker, K., et al. (1987) Proc. Natl. Acad. Science USA 84, 5459-5463

[2] Otto, D. & Unsicker, K (1990) J. Neuroscience 10, 1912-1921

[3] Reuss, B., et al. (2003) J. Neuroscience 23, 6404-6412

[4] Zechel, S., et al. (2006) Eur. J. Neuroscience 23, 1671-1675

[5] Irmady, K. & Unsicker, K. (2011) Glia 59: 708-719

[6] Jarosik, J. et al. (2011) Restor. Neurol. Neurosci. 29: 153-165

[7] Werner, S. et. al. (2011) J. Neurosci. Res. 89: 1605-1617

[8] Saunders, N.R. et al. (2016) Dev. Neurobiol. in press

[9] Baum, P. et al. (2016) Intl. J. Dev. Neuroscience, in press

 

 

Staff

Dr. Stella Shtukmaster