title: The Shh coreceptor Cdo is required for differentiation of midbrain dopaminergic neurons.
abstract: Sonic hedgehog (Shh) signaling is required for numerous developmental processes including specification of ventral cell types in the central nervous system such as midbrain dopaminergic (DA) neurons. The multifunctional coreceptor Cdo increases the signaling activity of Shh which is crucial for development of forebrain and neural tube. In this study, we investigated the role of Cdo in midbrain DA neurogenesis. Cdo and Shh signaling components are induced during neurogenesis of embryonic stem (ES) cells. Cdo(-/-) ES cells show reduced neuronal differentiation accompanied by increased cell death upon neuronal induction. In addition, Cdo(-/-) ES cells form fewer tyrosine hydroxylase (TH) and microtubule associated protein 2 (MAP2)-positive DA neurons correlating with the decreased expression of key regulators of DA neurogenesis, such as Shh, Neurogenin2, Mash1, Foxa2, Lmx1a, Nurr1 and Pitx3, relative to the Cdo(+/+) ES cells. Consistently, the Cdo(-/-) embryonic midbrain displays a reduction in expression of TH and Nurr1. Furthermore, activation of Shh signaling by treatment with Purmorphamine (Pur) restores the DA neurogenesis of Cdo(-/-) ES cells, suggesting that Cdo is required for the full Shh signaling activation to induce efficient DA neurogenesis.
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea.
authors.forename: Yu-Rim
authors.initials: YR
authors.lastname: Kwon
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea.
authors.forename: Myong-Ho
authors.initials: MH
authors.lastname: Jeong
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea.
authors.forename: Young-Eun
authors.initials: YE
authors.lastname: Leem
authors.affiliation: Research Center for Cell Fate Control, Sookmyung Women's University, Seoul 140-742, Republic of Korea.
authors.forename: Sang-Jin
authors.initials: SJ
authors.lastname: Lee
authors.affiliation: Department of Physiology, Sungkyunkwan University School of Medicine, Samsung Biomedical Research Institute, Suwon 440-746, Republic of Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: Research Center for Cell Fate Control, Sookmyung Women's University, Seoul 140-742, Republic of Korea. Electronic address: gbae@sm.ac.kr.
authors.forename: Gyu-Un
authors.initials: GU
authors.lastname: Bae
authors.affiliation: Department of Molecular Cell Biology, Sungkyunkwan University School of Medicine, Suwon 440-746, Republic of Korea. Electronic address: kangj01@skku.edu.
authors.forename: Jong-Sun
authors.initials: JS
authors.lastname: Kang
mesh_terms: D000818:Animals; D019521:Body Patterning; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage; D018920:Coculture Techniques; D059290:Dopaminergic Neurons / Q000187:drug effects / Q000378:metabolism*; D061252:Feeder Cells; D018507:Gene Expression Regulation, Developmental; D005838:Genotype; D053823:Hedgehog Proteins / Q000378:metabolism*; D008636:Mesencephalon / Q000187:drug effects / Q000196:embryology / Q000378:metabolism*; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D018345:Mice, Knockout; D009025:Morpholines / Q000494:pharmacology; D055495:Neurogenesis / Q000187:drug effects; D010641:Phenotype; D011687:Purines / Q000494:pharmacology; D015398:Signal Transduction; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: C510744:Cdon protein, mouse; D015815:Cell Adhesion Molecules; D053823:Hedgehog Proteins; D009025:Morpholines; D011687:Purines; C465570:Shh protein, mouse; D014157:Transcription Factors; C470893:purmorphamine