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Previous Article | Next Article
The Journal of Neuroscience, December 15, 2001, 21(24):9814-9823
Transcription Factor Expression and Notch-Dependent Regulation of Neural Progenitors in the Adult Rat Spinal Cord
Shin-ichi Yamamoto1, 2, Motoshi Nagao1, Michiya Sugimori1, Hidetaka Kosako1, Hirofumi Nakatomi1, 3, Naoya Yamamoto1, 2, Hirohide Takebayashi4, Yo-ichi Nabeshima4, 7, Toshio Kitamura5, Gerry Weinmaster6, Kozo Nakamura2, and Masato Nakafuku1, 7 Departments of 1 Neurobioloy, 2 Orthopaedic Surgery, and 3 Neurosurgery, The University of Tokyo Graduate School of Medicine, Tokyo 113-0033, Japan, 4 Department of Pathology and Tumor Biology, University of Kyoto Graduate School of Medicine, Kyoto 606-8501, Japan, 5 Department of Hematopoietic Factors, Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan, 6 Department of Biological Chemistry, University of California at Los Angeles School of Medicine, Los Angeles, California 90095-1737, and 7 Core Research for Evolutional Science and Technology, Japan Science and Technology Cooperation, Tokyo 105-0011, Japan
Recent studies have demonstrated that neural stem cells and other progenitors are present in the adult CNS. Details of their properties, however, remain poorly understood. Here we examined the properties and control mechanisms of neural progenitors in the adult rat spinal cord at the molecular level. Adult and embryonic progenitors commonly expressed various homeodomain-type (Pax6, Pax7, Nkx2.2, and Prox1) and basic helix-loop-helix (bHLH)-type (Ngn2, Mash1, NeuroD1, and Olig2) transcriptional regulatory factors in vitro. Unlike their embryonic counterparts, however, adult progenitors could not generate specific neurons that expressed markers appropriate for spinal motoneurons or interneurons, including Islet1, Lim1, Lim3, and HB9. Cells expressing the homeodomain factors Pax6, Pax7, and Nkx2.2 also emerged in vivo in response to injury and were distributed in unique patterns in the lesioned spinal cord. However, neither the expression of the neurogenic bHLH factors including Ngn2, Mash1, and NeuroD1 nor subsequent generation of new neurons could be detected in injured tissue. Our results suggest that signaling through the cell-surface receptor Notch is involved in this restriction. The expression of Notch1 in vivo was enhanced in response to injury. Furthermore, activation of Notch signaling in vitro inhibited differentiation of adult progenitors, whereas attenuation of Notch signals and forced expression of Ngn2 significantly enhanced neurogenesis. These results suggest that both the intrinsic properties of adult progenitors and local environmental signals, including Notch signaling, account for the limited regenerative potential of the adult spinal cord.
Key words: neural progenitor; stem cell; spinal cord; adult neurogenesis; Notch signaling; transcription factor; injury; regeneration
Copyright © 2001 Society for Neuroscience 0270-6474/01/21249814-10$05.00/0
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