title: Cortical-layer-specific effects of PACAP and tPA on interneuron migration during post-natal development of the cerebellum.
abstract: During early post-natal development of the cerebellum, granule neurons (GN) execute a centripetal migration toward the internal granular layer, whereas basket and stellate cells (B/SC) migrate centrifugally to reach their final position in the molecular layer (ML). We have previously shown that pituitary adenylate cyclase-activating polypeptide (PACAP) stimulates in vitro the expression and release of the serine protease tissue-type plasminogen activator (tPA) from GN, but the coordinated role of PACAP and tPA during interneuron migration has not yet been investigated. Here, we show that endogenous PACAP is responsible for the transient arrest phase of GN at the level of the Purkinje cell layer (PCL) but has no effect on B/SC. tPA is devoid of direct effect on GN motility in vitro, although it is widely distributed along interneuron migratory routes in the ML, PCL, and internal granular layer. Interestingly, plasminogen activator inhibitor 1 reduces the migration speed of GN in the ML and PCL, and that of B/SC in the ML. Taken together, these results reveal for the first time that tPA facilitates the migration of both GN and fast B/SC at the level of their intersection in the ML through degradation of the extracellular matrix. Crucial role of tissue plasminogen activator (tPA) in interneuron migration. Interneuron migration is a critical step for normal establishment of neuronal network. This study indicates that, in the post-natal cerebellum, tPA facilitates the opposite migration of immature excitatory granule neurons (GN) and immature inhibitory basket/stellate cells (B/SC) along the same migratory route. These data show that tPA exerts a pivotal role in neurodevelopment.
authors.affiliation: Inserm, PRIMACEN, Cell Imaging Platform of Normandy, Mont-Saint-Aignan, France; University of Rouen, Institute for Research and Innovation in Biomedicine (IRIB), Rouen, France; Inserm, U982, DC2N, Mont-Saint-Aignan, France; International Associated laboratory Samuel de Champlain, Inserm-INRS, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Raoult
authors.forename: Magalie
authors.initials: M
authors.lastname: Bénard
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Komuro
authors.forename: Alexis
authors.initials: A
authors.lastname: Lebon
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: David
authors.initials: D
authors.lastname: Vaudry
authors.forename: Ludovic
authors.initials: L
authors.lastname: Galas
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D002525:Cerebellar Cortex / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects* / Q000254:growth & development*; D003594:Cytoplasmic Granules / Q000378:metabolism; D005260:Female; D007150:Immunohistochemistry; D007395:Interneurons / Q000187:drug effects*; D008297:Male; D009924:Organ Culture Techniques; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000494:pharmacology*; D010958:Plasminogen / Q000494:pharmacology; D017395:Plasminogen Activator Inhibitor 1 / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D010959:Tissue Plasminogen Activator / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D017395:Plasminogen Activator Inhibitor 1; D010958:Plasminogen; D010959:Tissue Plasminogen Activator
keywords: PACAP; basket and stellate cells; cerebellum; granule neurons; interneuron migration; tPA