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The Journal of Neuroscience, October 10, 2007, 27(41):10924-10934; doi:10.1523/JNEUROSCI.1423-07.2007

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Development/Plasticity/Repair
Origin of Climbing Fiber Neurons and Their Developmental Dependence on Ptf1a

Mayumi Yamada,¹ Mami Terao,¹ Toshio Terashima,² Tomoyuki Fujiyama,¹ Yoshiya Kawaguchi,³ Yo-ichi Nabeshima,¹ and Mikio Hoshino^1,4

¹Department of Pathology and Tumor Biology, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8501, Japan, ²Division of Anatomy and Neurobiology, Department of Neuroscience, Kobe University Graduate School of Medicine, Kobe 650-0017, Japan, ³Department of Surgery and Surgical Basic Science, Kyoto University Graduate School of Medicine, Sakyo-ku, Kyoto 606-8507, Japan, and ⁴Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Kodaira, Tokyo 187-8502, Japan

Correspondence should be addressed to Mikio Hoshino, Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan. Email: hoshino{at}ncnp.go.jp

Climbing fiber (CF) neurons in the inferior olivary nucleus (ION) extend their axons to Purkinje cells, playing a crucial role in regulating cerebellar function. However, little is known about their precise place of birth and developmental molecular machinery. Here, we describe the origin of the CF neuron lineage and the involvement of Ptf1a (pancreatic transcription factor 1a) in CF neuron development. Ptf1a protein was found to be expressed in a discrete dorsolateral region of the embryonic caudal hindbrain neuroepithelium. Because expression of Ptf1a is not overlapping other transcription factors such as Math1 (mouse atonal homolog 1) and Neurogenin1, which are suggested to define domains within caudal hindbrain neuroepithelium (Landsberg et al., 2005), we named the neuroepithelial region the Ptf1a domain. Analysis of mice that express ß-galactosidase from the Ptf1a locus revealed that CF neurons are derived from the Ptf1a domain. In contrast, retrograde labeling of precerebellar neurons indicated that mossy fiber neurons are not derived from Ptf1a-expressing progenitors. We could observe a detailed migratory path of CF neurons from the Ptf1a domain to the ION during embryogenesis. In Ptf1a null mutants, putative immature CF neurons produced from this domain were unable to migrate or differentiate appropriately, resulting in a failure of ION formation. Apoptotic cells were observed in the mutant hindbrain. Furthermore, the fate of some cells in the Ptf1a lineage were changed to mossy fiber neurons in Ptf1a null mutants. These findings clarify the precise origin of CF neurons and suggest that Ptf1a controls their fate, survival, differentiation, and migration during development.

Key words: bHLH; cell fate; glutamatergic neurons; hindbrain; transcription factor; inferior olive

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Received March 29, 2007; revised Aug. 18, 2007; accepted Aug. 20, 2007.

Correspondence should be addressed to Mikio Hoshino, Department of Biochemistry and Cellular Biology, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawa-Higashi, Kodaira, Tokyo 187-8502, Japan. Email: hoshino{at}ncnp.go.jp

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Ptf1a Is a Molecular Determinant for Both Glutamatergic and GABAergic Neurons in the Hindbrain

Kimberly A. Aldinger and Gina E. Elsen
J. Neurosci. 2008 28: 338-339. [Full Text]  

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