Effects of growth/differentiation factor 5 on the survival and morphology of embryonic rat midbrain dopaminergic neurones in vitro.
Growth/differentiation factor 5 (GDF5) is a member of the transforming growth factor-beta superfamily that is expressed in the developing CNS, including the ventral mesencephalon (VM). GDF5 has been shown to increase the survival of dopaminergic neurones in animal models of Parkinson's disease. This study was aimed at characterising the effects of GDF5 on dopaminergic neurones in vitro. Treatment with GDF5 induced a three-fold increase in the number of dopaminergic neurones in embryonic day 14 rat VM cultures after six days in vitro. A significant increase was also observed in the numbers of astrocytes in GDF5-treated cultures. GDF5 treatment also had significant effects on the morphology of dopaminergic neurones in these cultures; total neurite length, number of branch points and somal area were all significantly increased after six days in vitro. Analysis of neurite length and numbers of branch points at each level of the neuritic field revealed that the most pronounced effects of GDF5 were on the secondary and tertiary levels of the neuritic field. The specific type I receptor for GDF5, bone morphogenetic protein receptor (BMPR)-Ib, was found to be strongly expressed in freshly-dissected E14 VM tissue, but its expression was lost with increasing time in culture. Accordingly, treatment with GDF5 for 24 h from the time of plating induced increases in the numbers of dopaminergic neurones, while treatment with GDF5 for 24 h after six days in vitro did not. This study shows that GDF5 can promote both the survival and morphological differentiation of VM dopaminergic neurones in vitro, lending support to its potential as a candidate dopaminergic neurotrophin for use in the treatment of Parkinson's disease.
O'Keeffe
Gerard W
GW
Department of Neuroscience/Anatomy, Biosciences Research Institute, National University of Ireland Cork (NUIC), Cork, Ireland.
Dockery
Peter
P
Sullivan
Aideen M
AM
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000502:physiology; D052005:Bone Morphogenetic Protein Receptors, Type I; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D002454:Cell Differentiation / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D004298:Dopamine / Q000378:metabolism*; D004334:Drug Administration Schedule; D055428:Growth Differentiation Factor 5; D008636:Mesencephalon / Q000166:cytology / Q000187:drug effects* / Q000196:embryology*; D016501:Neurites / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D010300:Parkinson Disease / Q000188:drug therapy; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017978:Receptors, Growth Factor / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D019485:Bone Morphogenetic Proteins; D055428:Growth Differentiation Factor 5; D017978:Receptors, Growth Factor; D017346:Protein Serine-Threonine Kinases; D052005:Bone Morphogenetic Protein Receptors, Type I; D004298:Dopamine