title: Altered cerebellum development and impaired motor coordination in mice lacking the Btg1 gene: Involvement of cyclin D1.
abstract: Cerebellar granule neurons develop postnatally from cerebellar granule precursors (GCPs), which are located in the external granule layer (EGL) where they massively proliferate. Thereafter, GCPs become postmitotic, migrate inward to form the internal granule layer (IGL), further differentiate and form synapses with Purkinje cell dendrites. We previously showed that the Btg family gene, Tis21/Btg2, is required for normal GCP migration. Here we investigated the role in cerebellar development of the related gene, Btg1, which regulates stem cell quiescence in adult neurogenic niches, and is expressed in the cerebellum. Knockout of Btg1 in mice caused a major increase of the proliferation of the GCPs in the EGL, whose thickness increased, remaining hyperplastic even after postnatal day 14, when the EGL is normally reduced to a few GCP layers. This was accompanied by a slight decrease of differentiation and migration of the GCPs and increase of apoptosis. The GCPs of double Btg1/Tis21-null mice presented combined major defects of proliferation and migration outside the EGL, indicating that each gene plays unique and crucial roles in cerebellar development. Remarkably, these developmental defects lead to a permanent increase of the adult cerebellar volume in Btg1-null and double mutant mice, and to impairment in all mutants, including Tis21-null, of the cerebellum-dependent motor coordination. Gain- and loss-of-function strategies in a GCP cell line revealed that Btg1 regulates the proliferation of GCPs selectively through cyclin D1. Thus, Btg1 plays a critical role for cerebellar maturation and function.
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy. Electronic address: manu.ceccarelli@gmail.com.
authors.forename: Manuela
authors.initials: M
authors.lastname: Ceccarelli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy. Electronic address: laura.micheli@cnr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Micheli
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy. Electronic address: dandrea.giorgio@gmail.com.
authors.forename: Giorgio
authors.initials: G
authors.lastname: D'Andrea
authors.affiliation: Neuroimmunology and Flow Cytometry Unit, Fondazione Santa Lucia, 00143 Rome, Italy. Electronic address: m.debardi@hsantalucia.it.
authors.forename: Marco
authors.initials: M
authors.lastname: De Bardi
authors.affiliation: Laboratory of Pediatric Oncology, Radboud University Medical Centre, 6500 HB, Nijmegen, The Netherlands. Electronic address: Blanca.Scheijen@radboudumc.nl.
authors.forename: Blanca
authors.initials: B
authors.lastname: Scheijen
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy. Electronic address: mariateresa.ciotti@cnr.it.
authors.forename: MariaTeresa
authors.initials: M
authors.lastname: Ciotti
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy. Electronic address: luca.leonardi@cnr.it.
authors.forename: Luca
authors.initials: L
authors.lastname: Leonardi
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy. Electronic address: siro.luvisetto@cnr.it.
authors.forename: Siro
authors.initials: S
authors.lastname: Luvisetto
authors.affiliation: Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy. Electronic address: felice.tirone@cnr.it.
authors.forename: Felice
authors.initials: F
authors.lastname: Tirone
mesh_terms: D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis; D002452:Cell Count; D002454:Cell Differentiation; D002465:Cell Movement; D049109:Cell Proliferation; D002531:Cerebellum / Q000254:growth & development* / Q000473:pathology / Q000503:physiopathology*; D019938:Cyclin D1 / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints; D017353:Gene Deletion; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism; D008527:Medulloblastoma / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity; D009363:Neoplasm Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: C489552:Btg1 protein, mouse; C489435:Btg2 protein, mouse; D017874:Immediate-Early Proteins; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; D019938:Cyclin D1
keywords: Cerebellar precursor cells; Cyclins; Neural cell migration; Neural cell proliferation; Postnatal neurogenesis