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Sie sind hier: Startseite Forschung Baader, Stephan Prof. Research

Research

Engrailed-2 as a regulator of neuronal wiring

Engrailed was first identified as a segment-polarity gene which is important for the segmentation and compartmentation of the invertebrate body plan and vertebrate organs. The mammalian homolog Engrailed-2 was shown to be important for the compartmentation of the cerebellar cortex. Compartmentation of central nervous tissue is considered to regulate region-specific wiring of the central nervous system. Whether and which role Engrailed-2 might have in regionalization of the cerebellar cortex is a major topic of our group. Since mutations within the En-2 gene has been associated with Autistic Spectrum Disorders, unraveling molecular mechanisms of Engrailed-2 involved in cerebellar wiring might help to understand aspects of pathogenesis of Autistic Phenotypes. Using a transgenic animal model, we found that Engrailed-2 is not only involved in the generation of a pool of precursor cells that give rise to Purkinje neurons of the cerebellum, but also regulates Purkinje cell differentiation and ingrowth of afferent fibers into the cerebellar cortex. By array analysis we could identify a set of genes which have a potential effect on process outgrowth and neurotransmission. Interestingly, some of these genes are discussed to be linked to Autism Spectrum Disorder. Using viral transfection systems in combination with slice cultures, dissociated primary cultures and transgenic approaches we further try to untangle the complex genetic network which underlies neurodevelopmental disorders.

Selected Readings:

 

  • Baader SL, Vogel MW, Zhang X, Sanlioglu S, Oberdick J (1999) Selective disruption of "late onset" sagittal banding patterns by ectopic expression of Engrailed-2 in cerebellar Purkinje cells. J Neurosci 19:5370-9
  • Jankowski J, Holst MI, Liebig C, Oberdick J, Baader SL (2004) Engrailed-2 negatively regulates the onset of perinatal Purkinje cell differentiation. J Comp Neurol 472:87-99
  • Jankowski J, Miething A, Schilling K, Oberdick J, Baader SL (2011)
    Cell death as a regulator of cerebellar histogenesis and compartmentation. Cerebellum 10: 373-392.

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Merlin, a tumor suppressor and regulator of neurite formation

The neurofibromatosis type 2 gene (nf2) was identified to be regulated in Engrailed-2 overexpressing mice. Mutations in nf2 are well known to cause malignant tumors in the central and peripheral nervous system. We have shown that the gene product of the nf2, Merlin, is expressed in neurons of the central nervous system. Merlin negatively regulates neurite outgrowth using the same phosphorylation site and potential signaling pathway used in tumor formation. In addition, an as yet disregarded isoform of Merlin, isoform 2, regulates intermediate filament spacing and thus regulates axon caliber and physiology. Patients harboring nf2 mutations show dysregulation of neurofilament phosphorylation and filament distance which suggests merlin isoform 2 to be responsible for polyneuropathies often observed in NF2 patients.


Selected Readings:
  • Schulz A, Geissler KJ, Kumar S, Leichsenring G, Morrison H, Baader SL (2010) Merlin inhibits neurite outgrowth in the central nervous system. J.Neurosci. 30:10177-86
  • Schulz A, Baader SL, ... Morrison H (2013) Merlin isoform 2 in neurofibromatosis type 2-associated polyneuropathy. Nat. Neurosci. 16: 426-433.

 

Gastrointestinal peptides as modulators of neurotransmission

Acetylcholine, norepinephrine, dopamine, GABA, glutamate, serotonin and endorphins are classical and the most significant neurotransmitters known. While GABA and glutamate support direct synaptic activity, neuromodulators such as serotonin and endorphins are secreted proteins which diffuse through large areas of the nervous system and affect multiple target neurons over long distances. Neuromodulators can both attenuate and intensify neurotransmission. In recent years, gastrointestinal peptides were shown to be expressed in the central nervous system and to intervene with synaptic transmission as neuromodulators. Interestingly, we have shown that cholecystokinine (CCK) is downregulated in cerebellar Purkinje cells after Engrailed-2 overexpression [6]. CCK regulates oxytocin expression in the pituitary gland, and it was shown that oxytocin and its signaling pathways influence social behavior in mammals including man. Patients suffering from Autistic Syndromes are characterized by social deficits. Gastrointenstinal peptides might therefore be important regulators of neurotransmission and cause Autistic syndromes via influencing oxytocin metabolism. This hypothesis is to be tested experimentally by animal models. As a paradigm, we will use the cerebellar system in which neuropeptidergic signaling can be specifically targeted by mutagenesis. In addition, we are aiming to expand our knowledge to the amygdalar system which is a central relay station in processing social behavior.

Selected Readings:

  • Holst MI, Maercker C, Pintea B, Masseroli M, Liebig C, Jankowski J, et al. (2008) Engrailed-2 regulates genes related to vesicle formation and transport in cerebellar Purkinje cells. Mol Cell Neurosci 38:495-504

Expertises:

  • Preparation of dissociated primary cell cultures as a central goal to investigate gene function in an in vivo-like system.
  • Preparation of slice cultures to follow neuronal development in "native" tissue.
  • Viral transduction systems to manipulate primary cultured cells.
  • Immunohistochemical analysis of wildtype and transgenic mice.
  • Microscopical and morphometrical analysis of tissues and cells.



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