Ptf1a, a bHLH transcriptional gene, defines GABAergic neuronal fates in cerebellum.
The molecular machinery governing glutamatergic-GABAergic neuronal subtype specification is unclear. Here we describe a cerebellar mutant, cerebelless, which lacks the entire cerebellar cortex in adults. The primary defect of the mutant brains was a specific inhibition of GABAergic neuron production from the cerebellar ventricular zone (VZ), resulting in secondary and complete loss of external germinal layer, pontine, and olivary nuclei during development. We identified the responsible gene, Ptf1a, whose expression was lost in the cerebellar VZ but was maintained in the pancreas in cerebelless. Lineage tracing revealed that two types of neural precursors exist in the cerebellar VZ: Ptf1a-expressing and -nonexpressing precursors, which generate GABAergic and glutamatergic neurons, respectively. Introduction of Ptf1a into glutamatergic neuron precursors in the dorsal telencephalon generated GABAergic neurons with representative morphological and migratory features. Our results suggest that Ptf1a is involved in driving neural precursors to differentiate into GABAergic neurons in the cerebellum.
Hoshino
Mikio
M
Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto 606-8501, Japan. mikio@lmls.med.kyoto-u.ac.jp
Nakamura
Shoko
S
Mori
Kiyoshi
K
Kawauchi
Takeshi
T
Terao
Mami
M
Nishimura
Yoshiaki V
YV
Fukuda
Akihisa
A
Fuse
Toshimitsu
T
Matsuo
Naoki
N
Sone
Masaki
M
Watanabe
Masahiko
M
Bito
Haruhiko
H
Terashima
Toshio
T
Wright
Christopher V E
CV
Kawaguchi
Yoshiya
Y
Nakao
Kazuwa
K
Nabeshima
Yo-Ichi
Y
D000367:Age Factors; D000818:Animals; D000831:Animals, Newborn; D001973:Bromodeoxyuridine / Q000378:metabolism; D064032:Calbindin 2; D064026:Calbindins; D002452:Cell Count / Q000379:methods; D016923:Cell Death / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology; D048429:Cell Size; D002531:Cerebellum / Q000002:abnormalities / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D004622:Embryo, Mammalian; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D049452:Green Fluorescent Proteins; D018257:Helix-Loop-Helix Motifs / Q000502:physiology*; D007150:Immunohistochemistry / Q000379:methods; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D020287:In Situ Nick-End Labeling / Q000379:methods; D066298:In Vitro Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D008959:Models, Neurological; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D009474:Neurons / Q000145:classification / Q000502:physiology*; D019696:Peptidylprolyl Isomerase / Q000502:physiology*; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D064030:S100 Calcium Binding Protein G / Q000378:metabolism; D001616:beta-Galactosidase / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
D064032:Calbindin 2; D064026:Calbindins; D005904:Glial Fibrillary Acidic Protein; D000072340:NIMA-Interacting Peptidylprolyl Isomerase; D012333:RNA, Messenger; D064030:S100 Calcium Binding Protein G; D049452:Green Fluorescent Proteins; D005680:gamma-Aminobutyric Acid; D001616:beta-Galactosidase; D019696:Peptidylprolyl Isomerase; C000606850:Pin1 protein, mouse; D001973:Bromodeoxyuridine