Survival of Developing Motor Neurons Mediated by Rho GTPase Signaling Pathway through Rho-Kinase

Kenta Kobayashi, Masanori Takahashi, Natsuki Matsushita, Jun Ichi Miyazaki, Masato Koike, Hiroyuki Yaginuma, Noriko Osumi, Kozo Kaibuchi, Kazuto Kobayashi

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74 Citations (Scopus)


A variety of neurons generated during embryonic development survive or undergo programmed cell death (PCD) at later developmental stages. Survival or death of developing neurons is generally considered to depend on trophic support from various target tissues. The small GTPase Rho regulates diverse cellular processes such as cell morphology, cell adhesion, cell motility, and apoptosis. Rho-dependent serine-threonine protein kinase (Rho-kinase-ROK-ROCK), one of the effector proteins, transmits signals for some Rho-mediated processes. Here, we report the in vivo role of the Rho signaling pathway through Rho-kinase during development of motor neurons (MNs) in the spinal cord. We performed conditional expression of a dominant-negative form for RhoA (RhoA DN) or for Rho-kinase (Rho-K DN) in transgenic mice by using the Cre-loxP system to suppress the activity of these signaling molecules in developing MNs. Expression of RhoA DN reduced the number of MNs in the spinal cord because of increased apoptosis while preserving the gross patterning of motor axons. Expression of Rho-K DN produced developmental defects similar to those observed in RhoA DN expression. In addition, analysis of transgenic mice expressing Rho-K DN showed that the increased apoptosis of MNs was induced at the early embryonic stages before the initiation of PCD, and that MN death at the late embryonic stages corresponding to the period of PCD was moderately enhanced in the transgenic mice. These findings indicate that the Rho signaling pathway, primarily through Rho-kinase, plays a crucial role in survival of spinal MNs during embryogenesis, particularly at the early developmental stages.

Original languageEnglish
Pages (from-to)3480-3488
Number of pages9
JournalJournal of Neuroscience
Issue number14
Publication statusPublished - 2004 Apr 7


  • Apoptosis
  • Axon patterning
  • Motor neuron
  • Neuronal survival
  • Programmed cell death
  • Small GTPase signaling


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