Research of the Unsicker group
Growth factors in development and functions of the nervous system
Klaus Unsicker
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. Unsicker
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
Development of a CNS-peripheral nervous system circuitry
Functions of Growth Differentiation Factor-15 (GDF-15)
Neuron survival and the roles of ERK
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
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 is still an open issue. We address this problem in a collaboration with the Kalcheim lab (Hebrew University Jerusalem) by single cell electroporations into delaminating NC cells following their subsequent migration into the target organs, i.e. sympathetic ganglia and adrenal gland, respectively. 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 [1,2]. Furthermore, we have analyzed, inter alia, the transcription factor network underlying chromaffin cell development [e.g. 3] and the role of BMP-4 for chromaffin cell fate determination and differentiation [4; 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 [5].
E15 embryonic chick adrenal gland showing expression of BMP-4 mRNA (blue) and TH mRNA.
Selected Publications
[1] Finotto, S. et al. (1999) Development 126, 2935-2944
[2] Gut, P. et al. (2005) Development 132, 4611-4619
[3] Huber, K. et al.. (2002) Development 129, 4729-4738 ]
[4] Huber, K. et al. (2008) Neural Development 3, 28 doi :191186/1749-8104-3-28
[5] Parlato, R. et al. (2009) Endocrinology 150, 1775-1781
Development of a CNS-peripheral nervous system circuitry
Neurons located in the spinal cord and in the brainstem link the central and peripheral portions of the autonomic nervous system, which is essential in the regulation of organ functions. The regulation of survival and differentiation of the CNS autonomic neurons in the spinal cord is not well understood. We have identified neurotrophin-4 [1] and ligands of the leukaemia inhibitory factor beta receptor [2] as crucially important neurotrophic factors for this neuron population and are currently studying additional candidate factors for these neurons. The figure below shows a cross-section of an embryonic mouse spinal cord, stained for choline acetyltransferase mRNA, a marker of cholinergic neurons. The smaller group of cholinergic neurons (blue/black) in the intermediolateral column of the spinal cord represents the CNS autonomic neurons currently under investigation.
Choline acetyltransferase mRNA in embryonic spinal cord
Selected Publications
[1] Roosen , A., et al. (2001) J. Neuroscience 21, 3073-3084
[2] Oberle, S., et al. (2006) J. Neuroscience 26, 1823-1832
Neuron survival and the roles of ERK
A classic perception of the molecular bases of the regulation of neuron survival and death implies ERK as an important trigger of neuron survival. Recent results from the laboratory seem to suggest that under certain experimental conditions induction of ERK may also accompany neuron death [1,2].
Selected Publications
[1] Subramaniam, S., et al. (2004) J. Cell Biol. 165, 357-369
[2] Subramaniam, S., et al. (2005) J. Neuroscience 25, 2838-2852
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 recently 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.
New neurons in dentate gyrus labeled with doublecortin
Selected Publications
[1] Strelau, J., et al. (2000) J. Neuroscience 20, 8597-8603
[2] Strelau J., et al., (2009) J. Neuroscience, in press
The neurotrophins brain-derived neurotrophic factor (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 -synuclein (red in figure below), a hallmark of Parkinson´s disease [1].
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].
Ongoing studies address roles of the cholinergic system and signalling via the NGF receptor trkA in limbic functions [cf. 3].
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
The lab 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] and astroglial cell differentiation [3]. Using FGF-2- and FGF receptor-deficient mice we are currently studying the physiological relevance of FGF signalling for midbrain dopaminergic neurons [4], FGF-dependent epigenetic regulation of astroglia differentiation [5], and the role of FGFs in animal models of major depression (in collaboration with the von Bohlen lab, Greifswald, and the Gass lab, ZI Mannheim)
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., submitted
Staff
Dr. Alexei Egorov, Dr. Sandra Werner, Stella Shtukmaster, M.Sc., Sabrina Walter, M.Sc., N.N., N.N.