title: A marked paucity of granule cells in the developing cerebellum of the Npc1(-/-) mouse is corrected by a single injection of hydroxypropyl-β-cyclodextrin.
abstract: In this study we show that postnatal development of cerebellar granule neurons (GNs) is defective in Npc1(-/-) mice. Compared to age-matched wild-type littermates, there is an accelerated disappearance of the external granule layer (EGL) in these mice. This is due to a premature exit from the cell cycle of GN precursors residing at the level of the EGL. As a consequence, the size of cerebellar lobules of these mice displays a 20%-25% reduction compared to that of age-matched wild-type mice. This size reduction is detectable at post-natal day 28 (PN28), when cerebellar GN development is completed while signs of neuronal atrophy are not yet apparent. Based on the analysis of EGL thickness and the determination of proliferating GN fractions at increasing developmental times (PN8-PN14), we trace the onset of this GN developmental defect during the second postnatal week. We also show that during this developmental time Shh transcripts undergo a significant reduction in Npc1(-/-) mice compared to age-matched wild-type mice. In light of the mitogenic activity of Shh on GNs, this observation further supports the presence of defective GN proliferation in Npc1(-/-) mice. A single injection of hydroxypropyl-β-cyclodextrin at PN7 rescues this defect, restoring the normal patterns of granule neuron proliferation and cerebellar lobule size. To our knowledge, these findings identify a novel developmental defect that was underappreciated in previous studies. This defect was probably overlooked because Npc1 loss-of-function does not affect cerebellar foliation and causes the internal granule layer and molecular layer to decrease proportionally, giving rise to a normally appearing, yet harmoniously smaller, cerebellum.
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, 00185 Rome, Italy.
authors: S
authors: S
authors: Nusca
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, 00185 Rome, Italy.
authors: S
authors: S
authors: Canterini
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, 00185 Rome, Italy.
authors: G
authors: G
authors: Palladino
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, 00185 Rome, Italy.
authors: F
authors: F
authors: Bruno
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, 00185 Rome, Italy.
authors: F
authors: F
authors: Mangia
authors: Department of Pediatrics, University of AZ, Tucson AZ85724-5073, USA.
authors: R P
authors: RP
authors: Erickson
authors: Department of Psychology, Section of Neuroscience and "Daniel Bovet" Neurobiology Research Center, Sapienza University of Rome, 00185 Rome, Italy. Electronic address: mariateresa.fiorenza@uniroma1.it.
authors: M T
authors: MT
authors: Fiorenza
mesh_terms: D000073738:2-Hydroxypropyl-beta-cyclodextrin; D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002531:Cerebellum / Q000187:drug effects* / Q000254:growth & development* / Q000503:physiopathology; D053823:Hedgehog Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008938:Mitosis / Q000187:drug effects / Q000502:physiology; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D000077296:Niemann-Pick C1 Protein; D009929:Organ Size; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D047392:beta-Cyclodextrins / Q000494:pharmacology*
chemical_list: D053823:Hedgehog Proteins; D047908:Intracellular Signaling Peptides and Proteins; D018696:Neuroprotective Agents; D000077296:Niemann-Pick C1 Protein; C106831:Npc1 protein, mouse; D011506:Proteins; D012333:RNA, Messenger; C465570:Shh protein, mouse; D047392:beta-Cyclodextrins; D000073738:2-Hydroxypropyl-beta-cyclodextrin
keywords: Cerebellum; Granule neuron proliferation; Hydroxypropyl-β-cyclodextrin; Niemann Pick C1