Primary cilia are critical for Sonic Hedgehog-mediated dopaminergic neurogenesis in the embryonic midbrain

• Verfasst von: Gazea, Mary [VerfasserIn]
• Verfasst von: Tasouri, Evangelia [VerfasserIn]
• Verfasst von: Gojak, Christian P. [VerfasserIn]
• Verfasst von: Kurtulmus, Bahtiyar [VerfasserIn]
• Verfasst von: Spatz, Joachim P. [VerfasserIn]
• Verfasst von: Pereira, Gislene [VerfasserIn]
• Titel: Primary cilia are critical for Sonic Hedgehog-mediated dopaminergic neurogenesis in the embryonic midbrain
• Verf.angabe: Mary Gazea, Evangelia Tasouri, Marianna Tolve, Viktoria Bosch, Anna Kabanova, Christian Gojak, Bahtiyar Kurtulmus, Orna Novikov, Joachim Spatz, Gislene Pereira, Wolfgang Hübner, Claude Brodski, Kerry L. Tucker, Sandra Blaess
• Jahr: 2016
• Jahr des Originals: 2015
• Umfang: 17 S.
• Fussnoten: Online published: 2 November 2015 ; Gesehen am 18.05.2017
• Titel Quelle: Enthalten in: Developmental biology
• Ort Quelle: Amsterdam [u.a.] : Elsevier, 1959
• Jahr Quelle: 2016
• Band/Heft Quelle: 409(2016), 1, Seite 55-71
• ISSN Quelle: 1095-564X
• DOI: doi:10.1016/j.ydbio.2015.10.033
• Datenträger: Online-Ressource
• Sprache: eng
• Sach-SW: Dopaminergic neurons
• Sach-SW: Ift88
• Sach-SW: Intraflagellar transport
• Sach-SW: Midbrain
• Sach-SW: Primary cilia
• Sach-SW: Shh
• K10plus-PPN: 1558767827

Abstract

Midbrain dopaminergic (mDA) neurons modulate various motor and cognitive functions, and their dysfunction or degeneration has been implicated in several psychiatric diseases. Both Sonic Hedgehog (Shh) and Wnt signaling pathways have been shown to be essential for normal development of mDA neurons. Primary cilia are critical for the development of a number of structures in the brain by serving as a hub for essential developmental signaling cascades, but their role in the generation of mDA neurons has not been examined. We analyzed mutant mouse lines deficient in the intraflagellar transport protein IFT88, which is critical for primary cilia function. Conditional inactivation of Ift88 in the midbrain after E9.0 results in progressive loss of primary cilia, a decreased size of the mDA progenitor domain, and a reduction in mDA neurons. We identified Shh signaling as the primary cause of these defects, since conditional inactivation of the Shh signaling pathway after E9.0, through genetic ablation of Gli2 and Gli3 in the midbrain, results in a phenotype basically identical to the one seen in Ift88 conditional mutants. Moreover, the expansion of the mDA progenitor domain observed when Shh signaling is constitutively activated does not occur in absence of Ift88. In contrast, clusters of Shh-responding progenitors are maintained in the ventral midbrain of the hypomorphic Ift88 mouse mutant, cobblestone. Despite the residual Shh signaling, the integrity of the mDA progenitor domain is severely disturbed, and consequently very few mDA neurons are generated in cobblestone mutants. Our results identify for the first time a crucial role of primary cilia in the induction of mDA progenitors, define a narrow time window in which Shh-mediated signaling is dependent upon normal primary cilia function for this purpose, and suggest that later Wnt signaling-dependent events act independently of primary cilia.