Püschel, Andeas, Prof. Dr. rer. nat.
Institut für Molekulare Zellbiologie
Tel: + 49 - 251 - 83 - 23841
Fax: + 49 - 251 - 83 - 24723
Püschel, Andeas, Prof. Dr. rer. nat.
- Studium der Biologie: Universität Bonn und Heidelberg
- Promotion: Universität Heidelberg; MPI f. biophysikalische Chemie, Göttingen
- Postdoctoral research associate: University of Oregon, Institute of Neuroscience, Eugene (Oregon, USA)
- Gruppenleiter am MPI für Hirnforschung, Frankfurt
- Habilitation in Biochemie: Universität Frankfurt
- Professor für Molekularbiologie an der WWU Münster
Molekular - und Zellbiologie
Entwicklung des Nervensystems
Entwicklung der neuronalen Polarität
Development of neuronal polarity (Funding: SPP 1111, GRK 1050)
The establishment of a polarized morphology and the functional specialization of different cellular compartiments are essential steps in the differentiation of neurons. However, the initial signals that establish a cellular asymmetry and the pathways that subsequently translate this asymmetry into the development of multiple dendrites and a single axon are largely unknown. We use primary cultures of dissociated hippocampal neurons as a model system to elucidate the molecular mechanisms that establish the asymmetric organization of cellular structures. We are investigating the role of different GTPases in the establishment of neuronal polarity to understand the initial events that determine which neurite becomes the axon. Our results show that the sequential activity of the GTPases Rap1B and Cdc42 is essential for the development of neuronal polarity. Initially, these GTPases are present in all neurites of unpolarized neurons but become restricted to a single neurite of late stage 2 neurons. Cdc42 coordinates the activity of different effectors and Rho-family GTPases to execute a program that results in the differentiation of neurons with molecularly distinct dendrites and axons.
Future projects will have to address the following questions:
1) How are GTPases and the Par complex restricted to a single neurite?
2) What are the pathways through which Cdc42 polarizes the cytoskeleton of neurons and specifies axonal identity?
3) What is the role of motor proteins and directed intracellular transport in the polarization of neurons?
Molecular analysis of signal transduction pathways involved in the guidance of axons (Funding: SFB 629, SFB 492)
The wiring of the nervous system is established through a progressive refinement of the choices made by a growing axon. The growth cone is a highly motile structure at the tip of the axon that integrates the multitude of signals present in its environment and translates these signals into structural changes of the cytoskeleton that determine the rate and direction of extension. The semaphorins represent the largest family of guidance cues identified so far. They function mainly as chemorepellents that direct axons away from tissues marked by their expression, but can also act as chemoattractants in some cases. The repulsive effects of the secreted semaphorins is mediated by a receptor complex that contains Neuropilin-1 (Nrp-1) or Nrp-2 as the ligand-binding subunit and an A-type plexin as the signal transducing subunit. At least two signaling pathways are involved in the response to these semaphorins. One includes the small GTPase Rac and leads to the depolymerization of actin filaments. GTPases act as molecular switches that regulate multiple cellular processes by activating downstream effectors when in the GTP-bound form.
We are using a combination of molecular, biochemical, genetic and cell biological methods to understand the role of GTPases in the response to semaphorins in primary neurons and transgenic mice. In addition, we investigate the changes in cytoskeletal dynamics in life growth cones as they respond to Sema3A.
Sprecher des DFG Graduiertenkollegs "Molekulare Zelldynamik" (GRK 1050)
- . . ‘The loss of the kinases SadA and SadB results in early neuronal apoptosis and a reduced number of progenitors.’ PLoS One 13.
- . ‘Membrane-binding and activation of LKB1 by phosphatidic acid is essential for development and tumor suppression.’ Nat. Comms. 8: 15747.
- . . ‘Rap1 GTPases Are Master Regulators of Neural Cell Polarity in the Developing Neocortex.’ Cereb. Cortex 27: 1253-1269.
- 10.1515/hsz-2016-0165. . ‘Regulation of Rap GTPases in mammalian neurons.’ Biological Chemistry 397, No. 10: 1055-1069. doi:
- 10.1371/journal.pone.0154174. . ‘C3G/Rapgef1 is required in multipolar neurons for the transition to a bipolar morphology during cortical development.’ PLoS ONE 11, No. 4. doi:
- . . ‘Persistence of the cell-cycle checkpoint kinase Wee1 in SadA- and SadB-deficient neurons disrupts neuronal polarity.’ JOURNAL OF CELL SCIENCE 123, No. 2: 286-294.
- . . ‘Phosphorylation of the Par Polarity Complex Protein Par3 at Serine 962 Is Mediated by Aurora A and Regulates Its Function in Neuronal Polarity.’ JOURNAL OF BIOLOGICAL CHEMISTRY 284, No. 48: 33571-33579.
- . . ‘The stimulation of dendrite growth by Sema3A requires integrin engagement and focal adhesion kinase.’ JOURNAL OF CELL SCIENCE 122, No. 12: 2034-2042.
- . . ‘Rnd1 regulates axon extension by enhancing the microtubule destabilizing activity of SCG10 (vol 284, pg 363, 2009).’ JOURNAL OF BIOLOGICAL CHEMISTRY 284, No. 23: 16060-16060.
- . . ‘Rnd1 Regulates Axon Extension by Enhancing the Microtubule Destabilizing Activity of SCG10.’ JOURNAL OF BIOLOGICAL CHEMISTRY 284, No. 1: 363-371.
- . . ‘Rheb and mTOR Regulate Neuronal Polarity through Rap1B.’ JOURNAL OF BIOLOGICAL CHEMISTRY 283, No. 48: 33784-33792.
- . . ‘GTPases in semaphorin signaling.’ SEMIAPHORINS: RECEPTOR AND INTRACELLULAR SIGNALING MECHANISMS 600: 12-23.
- . . ‘The rodent Four-jointed ortholog Fjx1 regulates dendrite extension.’ DEVELOPMENTAL BIOLOGY 312, No. 1: 461-470.
- . . ‘Ubiquitination of the GTPase Rap1B by the ubiquitin ligase Smurf2 is required for the establishment of neuronal polarity.’ EMBO JOURNAL 26, No. 5: 1410-1422.
- . . ‘GTPases and the control of neuronal polarity.’ METHODS IN ENZYMOLOGY, 406: 715-727.
- . . ‘Dual functional activity of semaphorin 3B is required for positioning the anterior commissure (.’ NEURON 48, No. 4: 699-699.
- . . ‘Dual functional activity of semaphorin 3B is required for positioning the anterior commissure.’ NEURON 48, No. 1: 63-75.
- . . ‘Semaphorin 4B interacts with the post-synaptic density protein PSD-95/SAP90 and is recruited to synapses through a C-terminal PDZ-binding motif.’ FEBS LETTERS 579, No. 17: 3821-3828.
- . . ‘The sequential activity of the GTPases Rap1B and Cdc42 determines neuronal polarity.’ NATURE NEUROSCIENCE 7, No. 9: 923-929.
- . . ‘Semaphorin 3A stimulates neurite extension and regulates gene expression in PC12 cells.’ JOURNAL OF BIOLOGICAL CHEMISTRY 279, No. 30: 30923-30926.
- . . ‘Plexin-B family members demonstrate non-redundant expression patterns in the developing mouse nervous system: an anatomical basis for morphogenetic effects of Sema4D during development.’ EUROPEAN JOURNAL OF NEUROSCIENCE 19, No. 10: 2622-2632.
- . . ‘Semaphorin 3A-mediated axon guidance regulates convergence and targeting of P2 odorant receptor axons.’ EUROPEAN JOURNAL OF NEUROSCIENCE 19, No. 7: 1800-1810.
- . . ‘Small monomeric GTPases in the development of neuronal polarity.’ JOURNAL OF NEUROCHEMISTRY 87: 164-164.
- . . ‘Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function.’ NATURE 424, No. 6951: 974-974.
- . . ‘Structure of the semaphorin-3A receptor binding module.’ NEURON 39, No. 4: 589-598.
- . . ‘Class 3 semaphorins control vascular morphogenesis by inhibiting integrin function.’ NATURE 424, No. 6947: 391-397.
- . . ‘The function of semaphorins during nervous system development.’ FRONTIERS IN BIOSCIENCE 8: S484S499.
- . . ‘The function of neuropilin/plexin complexes.’ NEUROPILIN: FROM NERVOUS SYSTEM TO VASCULAR AND TUMOR BIOLOGY 515: 71-80.
- . . ‘Cell type-specific expression of neuropilins in an MCA-occlusion model in mice suggests a potential role in post-ischemic brain remodeling.’ JOURNAL OF NEUROPATHOLOGY AND EXPERIMENTAL NEUROLOGY 61, No. 4: 339-350.
- . . ‘Antagonistic effects of Rnd1 and RhoD GTPases regulate receptor activity in semaphorin 3A-induced cytoskeletal collapse.’ JOURNAL OF NEUROSCIENCE 22, No. 2: 471-477.
- . . ‘Axonal surface molecules act in combination with semaphorin 3A during the establishment of corticothalamic projections.’ CEREBRAL CORTEX 11, No. 9: 891-891.
- . . ‘Differential responsiveness to the chemorepellent Semaphorin 3A distinguishes ipsi- and contralaterally projecting axons in the chick midbrain.’ DEVELOPMENTAL BIOLOGY 237, No. 2: 381-397.
- . . ‘Semaphorin 3A-vascular endothelial growth factor-165 balance mediates migration and apoptosis of neural progenitor cells by the recruitment of shared receptor.’ JOURNAL OF NEUROSCIENCE 21, No. 10: 3332-3341.
- . . ‘Axonal surface molecules act in combination with Semaphorin 3A during the establishment of corticothalamic projections.’ CEREBRAL CORTEX 11, No. 3: 278-285.
- . . ‘Patterning of olfactory sensory connections is mediated by extracellular matrix proteins in the nerve layer of the olfactory bulb.’ JOURNAL OF NEUROBIOLOGY 45, No. 4: 195-206.
- . . ‘Semaphorins as repellants and attractants in axon guidance.’ EUROPEAN JOURNAL OF NEUROSCIENCE 12: 267-267.
- . . ‘The semaphorin 3A receptor may directly regulate the activity of small GTPases.’ FEBS LETTERS 486, No. 1: 68-72.
- . . ‘Semaphorin 3A is required for guidance of olfactory axons in mice.’ JOURNAL OF NEUROSCIENCE 20, No. 20: 7691-7697.
- . . ‘Plexin/neuropilin complexes mediate repulsion by the axonal guidance signal semaphorin 3A.’ MECHANISMS OF DEVELOPMENT 93, No. 1-2: 95-104.
- . . ‘Sema3C and Netrin-1 differentially affect axon growth in the hippocampal formation.’ MOLECULAR AND CELLULAR NEUROSCIENCE 15, No. 2: 141-155.
- . . ‘Spatial distributions of guidance molecules regulate chemorepulsion and chemoattraction of growth cones.’ JOURNAL OF NEUROSCIENCE 20, No. 3: 1030-1035.
- . . ‘The chemorepulsive activity of secreted semaphorins is regulated by furin-dependent proteolytic processing.’ EMBO Journal 16, No. 20: 6077-6086. doi: 10.1093/emboj/16.20.6077.
- . . ‘Murine semaphorin D/collapsin is a member of a diverse gene family and creates domains inhibitory for axonal extension.’ Neuron 14, No. 5: 941-948. doi: 10.1016/0896-6273(95)90332-1.