title: Modulation of cell-cycle dynamics is required to regulate the number of cerebellar GABAergic interneurons and their rhythm of maturation.
abstract: The progenitors of cerebellar GABAergic interneurons proliferate up to postnatal development in the prospective white matter, where they give rise to different neuronal subtypes, in defined quantities and according to precise spatiotemporal sequences. To investigate the mechanisms that regulate the specification of distinct interneuron phenotypes, we examined mice lacking the G1 phase-active cyclin D2. It has been reported that these mice show severe reduction of stellate cells, the last generated interneuron subtype. We found that loss of cyclin D2 actually impairs the whole process of interneuron genesis. In the mutant cerebella, progenitors of the prospective white matter show reduced proliferation rates and enhanced tendency to leave the cycle, whereas young postmitotic interneurons undergo severe delay of their maturation and migration. As a consequence, the progenitor pool is precociously exhausted and the number of interneurons is significantly reduced, although molecular layer interneurons are more affected than those of granular layer or deep nuclei. The characteristic inside-out sequence of interneuron placement in the cortical layers is also reversed, so that later born cells occupy deeper positions than earlier generated ones. Transplantation experiments show that the abnormalities of cyclin D2(-/-) interneurons are largely caused by cell-autonomous mechanisms. Therefore, cyclin D2 is not required for the specification of particular interneuron subtypes. Loss of this protein, however, disrupts regulatory mechanisms of cell cycle dynamics that are required to determine the numbers of interneurons of different types and impairs their rhythm of maturation and integration in the cerebellar circuitry.
authors.affiliation: Neuroscience Institute of Turin (NIT), Department of Neuroscience, University of Turin, I-10125 Turin, Italy.
authors.forename: Ketty
authors.initials: K
authors.lastname: Leto
authors.forename: Alice
authors.initials: A
authors.lastname: Bartolini
authors.forename: Alessandra
authors.initials: A
authors.lastname: Di Gregorio
authors.forename: Daniele
authors.initials: D
authors.lastname: Imperiale
authors.forename: Annarita
authors.initials: A
authors.lastname: De Luca
authors.forename: Elena
authors.initials: E
authors.lastname: Parmigiani
authors.forename: Robert K
authors.initials: RK
authors.lastname: Filipkowski
authors.forename: Leszek
authors.initials: L
authors.lastname: Kaczmarek
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Rossi
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000254:growth & development / Q000378:metabolism*; D002453:Cell Cycle; D002465:Cell Movement; D056742:Cyclin D2 / Q000172:deficiency / Q000378:metabolism*; D007395:Interneurons / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C486196:Ccnd2 protein, mouse; D056742:Cyclin D2; D005680:gamma-Aminobutyric Acid