title: Cerebellar cortical lamination and foliation require cyclin A2.
abstract: The mammalian genome encodes two A-type cyclins, which are considered potentially redundant yet essential regulators of the cell cycle. Here, we tested requirements for cyclin A1 and cyclin A2 function in cerebellar development. Compound conditional loss of cyclin A1/A2 in neural progenitors resulted in severe cerebellar hypoplasia, decreased proliferation of cerebellar granule neuron progenitors (CGNP), and Purkinje (PC) neuron dyslamination. Deletion of cyclin A2 alone showed an identical phenotype, demonstrating that cyclin A1 does not compensate for cyclin A2 loss in neural progenitors. Cyclin A2 loss lead to increased apoptosis at early embryonic time points but not at post-natal time points. In contrast, neural progenitors of the VZ/SVZ did not undergo increased apoptosis, indicating that VZ/SVZ-derived and rhombic lip-derived progenitor cells show differential requirements to cyclin A2. Conditional knockout of cyclin A2 or the SHH proliferative target Nmyc in CGNP also resulted in PC neuron dyslamination. Although cyclin E1 has been reported to compensate for cyclin A2 function in fibroblasts and is upregulated in cyclin A2 null cerebella, cyclin E1 expression was unable to compensate for loss-of cyclin A2 function.
authors.affiliation: The Ohio State University College of Medicine, Department of Pathology, Division of Neuropathology, 4169 Graves Hall, 333 W 10th Avenue, Columbus, OH 43210, USA; University of California, San Francisco Department of Pathology, Division of Neuropathology, USA. Electronic address: jose.otero@osumc.edu.
authors.forename: José Javier
authors.initials: JJ
authors.lastname: Otero
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, USA; Department of Genetics, Harvard Medical School, USA; Tissue Engineering Lab, Department of Histology and Embryology, Center for Biostructure Research, Medical University of Warsaw, Poland.
authors.forename: Ilona
authors.initials: I
authors.lastname: Kalaszczynska
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, USA; Department of Genetics, Harvard Medical School, USA.
authors.forename: Wojciech
authors.initials: W
authors.lastname: Michowski
authors.affiliation: University of California, San Francisco Department of Pediatrics, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wong
authors.affiliation: The Ohio State University College of Medicine, Department of Pathology, Division of Neuropathology, 4169 Graves Hall, 333 W 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Patrick Edwin
authors.initials: PE
authors.lastname: Gygli
authors.affiliation: The Ohio State University College of Medicine, Department of Pathology, Division of Neuropathology, 4169 Graves Hall, 333 W 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Hamza Numan
authors.initials: HN
authors.lastname: Gokozan
authors.affiliation: University of California, San Francisco Department of Pediatrics, USA.
authors.forename: Amélie
authors.initials: A
authors.lastname: Griveau
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, USA; Department of Genetics, Harvard Medical School, USA.
authors.forename: Junko
authors.initials: J
authors.lastname: Odajima
authors.affiliation: The Ohio State University College of Medicine, Department of Pathology, Division of Neuropathology, 4169 Graves Hall, 333 W 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Catherine
authors.initials: C
authors.lastname: Czeisler
authors.affiliation: The Ohio State University College of Medicine, Department of Pathology, Division of Neuropathology, 4169 Graves Hall, 333 W 10th Avenue, Columbus, OH 43210, USA.
authors.forename: Fay Patsy
authors.initials: FP
authors.lastname: Catacutan
authors.affiliation: University of California, San Francisco Department of Pediatrics, USA.
authors.forename: Alice
authors.initials: A
authors.lastname: Murnen
authors.affiliation: Neuropathology, Ludwig-Maximilians-University, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Harvard Medical School, USA; Department of Genetics, Harvard Medical School, USA.
authors.forename: Piotr
authors.initials: P
authors.lastname: Sicinski
authors.affiliation: University of California, San Francisco Department of Pediatrics, USA.
authors.forename: David
authors.initials: D
authors.lastname: Rowitch
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D056751:Cyclin A2 / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D017403:In Situ Hybridization; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000378:metabolism
chemical_list: D056751:Cyclin A2
keywords: Brain malformation; CNS development; Cell cycle; Cyclin A1; Cyclin A2; Cyclin E1; DNA repair; External granule layer; Nestin