Overexpression of glial cell line-derived neurotrophic factor induces genes regulating migration and differentiation of neuronal progenitor cells.
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.
Pahnke
Jens
J
Department of Pathology, University Hospital Zürich, Switzerland. jens.pahnke@web.de
Mix
Eilhard
E
Knoblich
Rupert
R
Müller
Jana
J
Zschiesche
Marlies
M
Schubert
Beke
B
Koczan
Dirk
D
Bauer
Peter
P
Böttcher
Tobias
T
Thiesen
Hans-Jürgen
HJ
Lazarov
Ludmil
L
Wree
Andreas
A
Rolfs
Arndt
A
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
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