title: Overexpression of glial cell line-derived neurotrophic factor induces genes regulating migration and differentiation of neuronal progenitor cells.
abstract: The glial cell line-derived neurotrophic factor (GDNF) is involved in the development and maintenance of neural tissues. Mutations in components of its signaling pathway lead to severe migration deficits of neuronal crest stem cells, tumor formation, or ablation of the urinary system. In animal models of Parkinson's disease, GDNF has been recognized to be neuroprotective and to improve motor function when delivered into the cerebral ventricles or into the substantia nigra. Here, we characterize the network of 43 genes induced by GDNF overproduction of neuronal progenitor cells (ST14A), which mainly regulate migration and differentiation of neuronal progenitor cells. GDNF down-regulates doublecortin, Paf-ah1b (Lis1), dynamin, and alpha-tubulin, which are involved in neocortical lamination and cytoskeletal reorganization. Axonal guidance depends on cell-surface molecules and extracellular matrix proteins. Laminin, Mpl3, Alcam, Bin1, Id1, Id2, Id3, neuregulin1, the ephrinB2-receptor, neuritin, focal adhesion kinase (FAK), Tc10, Pdpk1, clusterin, GTP-cyclooxygenase1, and follistatin are genes up-regulated by GDNF overexpression. Moreover, we found four key enzymes of the cholesterol-synthesis pathway to be down-regulated leading to decreased farnesyl-pyrophospate production. Many proteins are anchored by farnesyl-derivates at the cell membrane. The identification of these GDNF-regulated genes may open new opportunities for directly influencing differentiation and developmental processes of neurons.
authors.affiliation: Department of Pathology, University Hospital Zürich, Switzerland. jens.pahnke@web.de
authors.forename: Jens
authors.initials: J
authors.lastname: Pahnke
authors.forename: Eilhard
authors.initials: E
authors.lastname: Mix
authors.forename: Rupert
authors.initials: R
authors.lastname: Knoblich
authors.forename: Jana
authors.initials: J
authors.lastname: Müller
authors.forename: Marlies
authors.initials: M
authors.lastname: Zschiesche
authors.forename: Beke
authors.initials: B
authors.lastname: Schubert
authors.forename: Dirk
authors.initials: D
authors.lastname: Koczan
authors.forename: Peter
authors.initials: P
authors.lastname: Bauer
authors.forename: Tobias
authors.initials: T
authors.lastname: Böttcher
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Thiesen
authors.forename: Ludmil
authors.initials: L
authors.lastname: Lazarov
authors.forename: Andreas
authors.initials: A
authors.lastname: Wree
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000235:genetics*; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects / Q000235:genetics*; D002472:Cell Transformation, Viral; D000089662:Doublecortin Protein; D015536:Down-Regulation; D019085:Fluorescent Antibody Technique, Direct; D005786:Gene Expression Regulation; D005809:Genes, Regulator; D051100:Glial Cell Line-Derived Neurotrophic Factor; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000235:genetics / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D012190:Retroviridae / Q000235:genetics; D013234:Stem Cells / Q000166:cytology / Q000378:metabolism*; D013696:Temperature; D015854:Up-Regulation
chemical_list: C000714848:Dcx protein, rat; D000089662:Doublecortin Protein; C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D012333:RNA, Messenger