RT Journal Article
SR Electronic
T1 Specification of Spatial Identities of Cerebellar Neuron Progenitors by Ptf1a and Atoh1 for Proper Production of GABAergic and Glutamatergic Neurons
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 4786
OP 4800
DO 10.1523/JNEUROSCI.2722-13.2014
VO 34
IS 14
A1 Mayumi Yamada
A1 Yusuke Seto
A1 Shinichiro Taya
A1 Tomoo Owa
A1 Yukiko U. Inoue
A1 Takayoshi Inoue
A1 Yoshiya Kawaguchi
A1 Yo-ichi Nabeshima
A1 Mikio Hoshino
YR 2014
UL http://www.jneurosci.org/content/34/14/4786.abstract
AB In the cerebellum, the bHLH transcription factors Ptf1a and Atoh1 are expressed in distinct neuroepithelial regions, the ventricular zone (VZ) and the rhombic lip (RL), and are required for producing GABAergic and glutamatergic neurons, respectively. However, it is unclear whether Ptf1a or Atoh1 is sufficient for specifying GABAergic or glutamatergic neuronal fates. To test this, we generated two novel knock-in mouse lines, Ptf1aAtoh1 and Atoh1Ptf1a, that are designed to express Atoh1 and Ptf1a ectopically in the VZ and RL, respectively. In Ptf1aAtoh1 embryos, ectopically Atoh1-expressing VZ cells produced glutamatergic neurons, including granule cells and deep cerebellar nuclei neurons. Correspondingly, in Atoh1Ptf1a animals, ectopically Ptf1a-expressing RL cells produced GABAergic populations, such as Purkinje cells and GABAergic interneurons. Consistent results were also obtained from in utero electroporation of Ptf1a or Atoh1 into embryonic cerebella, suggesting that Ptf1a and Atoh1 are essential and sufficient for GABAergic versus glutamatergic specification in the neuroepithelium. Furthermore, birthdating analyses with BrdU in the knock-in mice or with electroporation studies showed that ectopically produced fate-changed neuronal types were generated at temporal schedules closely simulating those of the wild-type RL and VZ, suggesting that the VZ and RL share common temporal information. Observations of knock-in brains as well as electroporated brains revealed that Ptf1a and Atoh1 mutually negatively regulate their expression, probably contributing to formation of non-overlapping neuroepithelial domains. These findings suggest that Ptf1a and Atoh1 specify spatial identities of cerebellar neuron progenitors in the neuroepithelium, leading to appropriate production of GABAergic and glutamatergic neurons, respectively.