Differential Regulation of Midbrain Dopaminergic Neuron Development by Wnt-1, Wnt-3a, and Wnt-5a

• Published in: Proceedings of the National Academy of Sciences - PNAS 2003-10, Vol.100 (22), p.12747-12752
• Main Authors: Castelo-Branco, Gonçalo, Wagner, Joseph, Rodriguez, Francisco J., Kele, Julianna, Sousa, Kyle, Rawal, Nina, Pasolli, Hilda Amalia, Fuchs, Elaine, Kitajewski, Jan, Arenas, Ernest
• Format: Article
• Language: English
• Subjects: Animals; b-Catenin; beta Catenin; Biological Sciences; Brain; Cell Differentiation; Cells, Cultured; Cellular biology; Cultured cells; Cytoskeletal Proteins - genetics; Cytoskeletal Proteins - physiology; Developmental biology; Female; Gene Expression Regulation, Developmental - physiology; Male; Medicin och hälsovetenskap; Mesencephalon - physiology; Messenger RNA; Mice; Midbrain; Mitogens - physiology; Neural stem cells; Neurons; Neurons - cytology; Neurons - physiology; Neuroscience; Nurr1 gene; Nurr1 nuclear receptors; Phenotypes; Physiological regulation; Proto-Oncogene Proteins - genetics; Rats; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; Stem cells; Trans-Activators - genetics; Trans-Activators - physiology; Wnt protein; Wnt Proteins; Wnt-1 gene; Wnt-3a gene; Wnt-5a gene; Wnt-5a Protein; Wnt1 Protein; Wnt2 Protein; Zebrafish Proteins
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1534900100

The Wnts are a family of glycoproteins that regulate cell proliferation, fate decisions, and differentiation. In our study, we examined the contribution of Wnts to the development of ventral midbrain (VM) dopaminergic (DA) neurons. Our results show that β-catenin is expressed in DA precursor cells and that β-catenin signaling takes place in these cells, as assessed in TOPGAL [Tcf optimal-promoter β-galactosidase] reporter mice. We also found that Wnt-1, -3a, and -5a expression is differentially regulated during development and that partially purified Wnts distinctively regulate VM development. Wnt-3a promoted the proliferation of precursor cells expressing the orphan nuclear receptor-related factor 1 (Nurr1) but did not increase the number of tyrosine hydroxylase-positive neurons. Instead, Wnt-1 and -5a increased the number of rat midbrain DA neurons in rat embryonic day 14.5 precursor cultures by two distinct mechanisms. Wnt-1 predominantly increased the proliferation of Nurr1+ precursors, up-regulated cyclins D1 and D3, and down-regulated p27 and p57 mRNAs. In contrast, Wnt-5a primarily increased the proportion of Nurr1+ precursors that acquired a neuronal DA phenotype and up-regulated the expression of Ptx3 and c-ret mRNA. Moreover, the soluble cysteine-rich domain of Frizzled-8 (a Wnt inhibitor) blocked endogenous Wnts and the effects of Wnt-1 and -5a on proliferation and the acquisition of a DA phenotype in precursor cultures. These findings indicate that Wnts are key regulators of proliferation and differentiation of DA precursors during VM neurogenesis and that different Wnts have specific and unique activity profiles.