Cerebellar cortical lamination and foliation require cyclin A2

• Published in: Developmental biology 2014-01, Vol.385 (2), p.328-339
• Main Authors: Otero, José Javier, Kalaszczynska, Ilona, Michowski, Wojciech, Wong, Michael, Gygli, Patrick Edwin, Gokozan, Hamza Numan, Griveau, Amélie, Odajima, Junko, Czeisler, Catherine, Catacutan, Fay Patsy, Murnen, Alice, Schüller, Ulrich, Sicinski, Piotr, Rowitch, David
• Format: Article
• Language: English
• Subjects: Animals; Brain malformation; Cell cycle; Cell Proliferation; Cerebral Cortex - cytology; Cerebral Cortex - embryology; Cerebral Cortex - metabolism; CNS development; Cyclin A1; Cyclin A2; Cyclin A2 - genetics; Cyclin A2 - metabolism; Cyclin A2 - physiology; Cyclin E1; DNA repair; External granule layer; In Situ Hybridization; Mice; Mice, Knockout; Mice, Transgenic; Nestin; Neural Stem Cells - metabolism
• ISSN: 0012-1606; 1095-564X
• DOI: 10.1016/j.ydbio.2013.10.019

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. •The developing postnatal cerebellum shows robust expression of cyclin A2.•Cyclin A2 expression is present in cycling neural progenitor cells and in terminally differentiated neurons.•Cyclin A2 loss results in dysmorphic cerebellum and PC dyslamination.•Cyclin A1 cannot compensate for cyclin A2 loss.•We propose that any defect in CGNP proliferation may lead to PC dyslamination.