title: GDNF is important for striatal organization and maintenance of dopamine neurons grown in the presence of the striatum.
abstract: Glial cell line-derived neurotrophic factor (GDNF) exerts neuroprotective and neurorestorative effects on neurons and GDNF plays a significant role in maintenance of the dopamine neurons utilizing grafting to create a nigrostriatal microcircuit of Gdnf knockout (Gdnf(-/-)) tissue. To further evaluate the role of GDNF on organization of the nigrostriatal system, single or double grafts of ventral mesencephalon (VM) and lateral ganglionic eminence (LGE) with mismatches in Gdnf genotypes were performed. The survival of single grafts was monitored utilizing magnetic resonance imaging (MRI) and cell survival and graft organization were evaluated with immunohistochemistry. The results revealed that the size of VM single grafts did not change over time independent of genotype, while the size of the LGE transplants was significantly reduced already at 2 weeks postgrafting when lacking GDNF. Lack of GDNF did not significantly affect the survival of tyrosine hydroxylase (TH)-positive neurons in single VM grafts. However, the survival of TH-positive neurons was significantly reduced in VM derived from Gdnf(+/+) when co-grafted with LGE from the Gdnf(-/-) tissue. In contrast, lack of GDNF in the VM portion of co-grafts had no effect on the survival of TH-positive neurons when co-grafted with LGE from Gdnf(+/+) mice. The TH-positive innervation of co-grafts was sparse when the striatal co-grafts were derived from the Gdnf(-/-) tissue while dense and patchy when innervating LGE producing GDNF. The TH-positive innervation overlapped with the organization of dopamine and cyclic AMP-regulated phosphoprotein-relative molecular mass 32,000 (DARPP-32)-positive neurons, that was disorganized in LGE lacking GDNF production. In conclusion, GDNF is important for a proper striatal organization and for survival of TH-positive neurons in the presence of the striatal tissue.
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Chermenina
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Schouten
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: N
authors.initials: N
authors.lastname: Nevalainen
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: F
authors.initials: F
authors.lastname: Johansson
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Orädd
authors.affiliation: Integrative Medical Biology, Umeå University, 901 87 Umeå, Sweden. Electronic address: ingrid.stromberg@umu.se.
authors.forename: I
authors.initials: I
authors.lastname: Strömberg
mesh_terms: D000818:Animals; D016380:Brain Tissue Transplantation; D002470:Cell Survival / Q000502:physiology; D003342:Corpus Striatum / Q000254:growth & development* / Q000502:physiology* / Q000601:surgery; D051937:Dopamine and cAMP-Regulated Phosphoprotein 32 / Q000378:metabolism; D059290:Dopaminergic Neurons / Q000502:physiology*; D005260:Female; D060005:Genotyping Techniques; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism*; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008636:Mesencephalon / Q000196:embryology / Q000502:physiology / Q000637:transplantation; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D051937:Dopamine and cAMP-Regulated Phosphoprotein 32; C495040:Gdnf protein, mouse; D051100:Glial Cell Line-Derived Neurotrophic Factor; C497929:Ppp1r1b protein, mouse; D014446:Tyrosine 3-Monooxygenase
keywords: DARPP-32; GDNF; GDNF knockout; dopamine; striatum; substantia nigra