Pleiotrophin exhibits a trophic effect on survival of dopaminergic neurons in vitro.
To understand what kind of trophic factors are up-regulated in dopamine (DA)-depleted striatum, we first analysed the up-regulation of mRNAs using a DNA microarray in DA-depleted striatum where DAergic inputs were denervated by 6-OHDA. We then investigated whether or not such trophic factors had an effect on cultured dopaminergic neurons. The microarray analysis revealed that pleiotrophin (PTN), glial-derived neurotopic factor (GDNF) and others were up-regulated in DA-depleted striatum. As PTN has been reported to have a wide range of trophic effects on neurons, we focused on the functional role of PTN in the present study. The increase in PTN mRNA was confirmed by Northern blotting at 1-3 weeks after the lesion, reaching a peak at 1 week. In embryonic day 15 mesencephalic neuron culture, PTN increased the number of tyrosine hydroxylase (TH) -positive neurons in a dose-dependent manner (125.2 +/- 2.0% of the control at 50 ng/mL), while a family protein, midkine (10 ng/mL) did not show any trophic effect (99.3 +/- 0.7%). In addition, the PTN effect on DAergic neurons was additive to the GDNF effect. As PTN did not increase the number of microtubule-associated protein-2 (MAP 2)-positive neurons or promote the proliferation of dopaminergic progenitors in a bromodeoxyuridine (BrdU) labelling study, the effect appeared to enhance the specific survival of dopaminergic neurons. Expression of PTN receptors (syndecan-3, PTP-zeta) was detected on the cultured mesencephalic neurons, and also up-regulated in DA-depleted striatum. The data indicate that PTN is up-regulated in DA-depleted striatum and exhibits a trophic effect specifically on the survival of cultured dopaminergic neurons.
Hida
Hideki
H
Department of Neurophysiology and Brain Science, Nagoya City University Graduate School of Medical Sciences, Kawasumi 1, Mizuho-Ku, Nagoya 467-8601, Japan. hhida@med.nagoya-cu.ac.jp
Jung
Cha-Gyun
CG
Wu
Chen-Zhen
CZ
Kim
Hye-Jung
HJ
Kodama
Yuji
Y
Masuda
Tadashi
T
Nishino
Hitoo
H
D000818:Animals; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D003342:Corpus Striatum / Q000166:cytology; D016207:Cytokines / Q000235:genetics* / Q000378:metabolism* / Q000494:pharmacology; D004298:Dopamine / Q000502:physiology*; D005260:Female; D015870:Gene Expression / Q000502:physiology; D066298:In Vitro Techniques; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000166:cytology* / Q000502:physiology*; D020411:Oligonucleotide Array Sequence Analysis; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism; D011509:Proteoglycans / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D053670:Syndecan-3; D015854:Up-Regulation
D002352:Carrier Proteins; D016207:Cytokines; D008562:Membrane Glycoproteins; D011509:Proteoglycans; D012333:RNA, Messenger; C508303:Sdc3 protein, rat; D053670:Syndecan-3; C066845:pleiotrophin; D017027:Protein Tyrosine Phosphatases; D004298:Dopamine