Balanced effect of PACAP and FasL on granule cell death during cerebellar development: a morphological, functional and behavioural characterization.
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.
Allais
Aurélie
A
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.
Burel
Delphine
D
Roy
Vincent
V
Arthaud
Sébastien
S
Galas
Ludovic
L
Isaac
Emma Rachel
ER
Desfeux
Arnaud
A
Parent
Bénédicte
B
Fournier
Alain
A
Chapillon
Pierre
P
Sherwood
Nancy McKeown
NM
Vaudry
Hubert
H
Gonzalez
Bruno José
BJ
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
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D012333:RNA, Messenger; D053148:Caspase 3; D001973:Bromodeoxyuridine