title: Balanced effect of PACAP and FasL on granule cell death during cerebellar development: a morphological, functional and behavioural characterization.
abstract: It is now established that the development of the CNS requires equilibrium between cell survival and apoptosis. Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts a powerful protective effect on cerebellar granule cells by inhibiting the caspase 3. In contrast, Fas ligand (FasL) plays an essential role during ontogenesis in eliminating supernumerary neurons by apoptosis. To determine if PACAP and FasL interact during cerebellar development, we characterized the effects of these factors on cerebellar morphogenesis and caspase 3 activity in PACAP+/+ and PACAP-/- mice. First, we demonstrated in vivo that PACAP is able to reverse the diminution of internal granule cell layer thickness induced by FasL in PACAP+/+ and PACAP-/- mice. Second, ex vivo and immunohistochemical studies revealed that interaction between FasL and PACAP occurs through the caspase 3 activity. Third, behavioural study showed a significant difference for the PACAP + FasL group in the righting reflex test at P8 which does not persist at P60. Finally, a time course study revealed that the pro-apoptotic effect of FasL characterized at P8 was followed by a progressive compensatory mechanism in caspase 3 activity and bromodeoxyuridine incorporation. These data suggest that PACAP and FasL interact during cerebellar development to control apoptosis of granule cells and may affect some motor cerebellar functions.
authors.affiliation: Inserm U982, European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, Laboratoire International Associé Samuel de Champlain, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Aurélie
authors.initials: A
authors.lastname: Allais
authors.forename: Delphine
authors.initials: D
authors.lastname: Burel
authors.forename: Vincent
authors.initials: V
authors.lastname: Roy
authors.forename: Sébastien
authors.initials: S
authors.lastname: Arthaud
authors.forename: Ludovic
authors.initials: L
authors.lastname: Galas
authors.forename: Emma Rachel
authors.initials: ER
authors.lastname: Isaac
authors.forename: Arnaud
authors.initials: A
authors.lastname: Desfeux
authors.forename: Bénédicte
authors.initials: B
authors.lastname: Parent
authors.forename: Alain
authors.initials: A
authors.lastname: Fournier
authors.forename: Pierre
authors.initials: P
authors.lastname: Chapillon
authors.forename: Nancy McKeown
authors.initials: NM
authors.lastname: Sherwood
authors.forename: Hubert
authors.initials: H
authors.lastname: Vaudry
authors.forename: Bruno José
authors.initials: BJ
authors.lastname: Gonzalez
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology*; D001973:Bromodeoxyuridine / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D048429:Cell Size / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology* / Q000187:drug effects / Q000254:growth & development*; D053222:Fas Ligand Protein / Q000378:metabolism* / Q000494:pharmacology; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics; D066298:In Vitro Techniques; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000172:deficiency / Q000378:metabolism* / Q000494:pharmacology; D011597:Psychomotor Performance / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D018709:Statistics, Nonparametric; D013997:Time Factors
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D053148:Caspase 3; D001973:Bromodeoxyuridine