Prof. Dr. Klaus Unsicker

MD 1968 University of Kiel, Germany,

Postdoctoral work at Universities of Lund, Sweden, Melbourne, Australia, and UCL, London, Research Fellow UC San Diego 1983/84,

NIH/NCI Bethesda 1989/90, Professor, University of Marburg, 1978-92, Professor of Anatomy and Cell Biology, IZN, Heidelberg, 1992 - 2009.  

Institute for Anatomy and Cell Biology, University of Freiburg, since 2009.

Growth factors in neural development

Current Research

Development of distinct cell phenotypes, neuron survival, network formation, and responses to lesions in the nervous system depend on the concerted actions of numerous, largely multifunctional growth factors. Ongoing projects in the group include the following: (1) specification of neural crest (NC) derived neuronal and neuroendocrine cells and their integration into neural circuitries, (2) functional characterization and signaling of a novel member of the TGF-ßs, GDF-15, (3) significance of neurotrophin signaling for the development and maintenance of CNS aminergic systems, and (4) roles of FGFs and TGF-ßs in neuronal and astroglial functions.

The NC as a paradigm for studying generation of cell diversity

The NC gives rise to diverse neuronal, endocrine, and mesenchymal cell types and, hence, is an excellent model for exploring mechanisms involved in the generation of cell diversity. We focus on the sympathoadrenal (SA) cell lineage, which gives rise to sympathetic neurons and neuroendocrine chromaffin cells. We have found that glucocorticoid signaling, contrary to a previous hypothesis, is not essential or sufficient for generating chromaffin cells. We are currently studying the roles of BMP-4 and transcription factors in the specification of chromaffin as opposed to neuronal cells using loss- and gain-of-function paradigms. The bhlh transcription factor MASH-1 is important for the development of a major subpopulation of chromaffin cells. BMP-4 is highly and persistently expressed in all locations, where chromaffin cells develop, suggesting that it may play a role, by itself or in synergy with other factors, in suppressing neuronal and promoting endocrine features in SA progenitors.

Development and maintenance of the neural circuitry that links CNS and peripheral portions of the sympathetic nervous system

Sympathetic neurons and chromaffin cells are innervated by preganglionic sympathetic neurons (PSN; Fig. 1) that are located in the spinal cord and develop from the same precursor pool as motoneurons. In contrast to the abundant information available for factors that affect motoneuron development, very little is known on PSN promoting factors. Using knockout mice we have established that the LIFRß and neurotrophin-4, but not FGF-2, are important for embryonic and postnatal, respectively, development of PSN neurons.

Fig. 1 Retrogradely traced IML neuronal cell bodies and processes (marked by arrowheads) extending towards the central canal (CC) of the spinal cord. Bar: 40 µm. By A. Schobe

Functional characterization and signaling of a novel member of the TGF-ßs, GDF-15

GDF-15 is a novel, distant member of the TGF-ßs with wide distribution in the CNS. As a trophic factor for midbrain dopaminergic neurons in vitro and in vivo it is at least as potent as GDNF. GDF-15 is prominently upregulated in lesioned neurons suggesting functions related to executing survival or death programs. On cerebellar granule neurons GDF-15 exerts its survival promoting effect through activation of the PI3K/Akt/GSK-3 pathway. A GDF-15 knockout mouse has been generated and is currently analyzed.

Significance of neurotrophin signaling for the development and maintenance of CNS aminergic systems

BDNF, NT-3, and NT-4 have been shown to be important regulators of the development and plasticity of the dopaminergic and serotonergic systems. We use aged trkB and trkC heterozygous knockout mice to analyze functional deficits related to these aminergic systems.

Roles of FGFs and TGF-ßs in neuronal and astroglial functions

We are studying the roles of FGF-2, -5, -9, and TGF-ß2 and -ß3 in the regulation of neuronal and astroglial development and functions in the adult. Using in vitro approaches and knockout mice we have found that FGFs regulate astroglial differentiation, gap junction communication, and blood-brain-barrier permeability in a region-specific fashion (Fig. 2). Concerning TGF-ßs we focus on the molecular bases of their synergistic roles with neurotrophins, GDNF, and FGF-2 in the regulation of neuron survival.

Fig. 2 GFAP-immunoreactive astrocytes and albumin extravasation in the cortex of FGF2/FGF5 deficient mouse mutants and wildtype littermates. Bars: 40µm (a, b) and 20 µm (c, d). By B. Reuss

Future Projects and Goals

Our long-term goal is to understand the hierarchies and interdependencies of molecules involved in the generation of cellular heterogeniety and cell-cell communication in the nervous system. Current work in the NC project suggests that SA progenitors destined to become neurons or chromaffin cells, respectively, may phenotypically segregate prior to reaching their final target sites. We are working on the identification of the GDF-15 receptor and hope to obtain additional cues as to its functions from the current analysis of the GDF-15 knockout. We will expand on the use of transgenic animal models to understand the roles of FGFs and TGF-ßs not only in development, but also in the context of lesions with clinical relevance.

Selected Publications

Letzte Änderung: Fri, 20.04.2018
zum Seitenanfang/up