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The Journal of Neuroscience, April 7, 2004, 24(14):3480-3488; doi:10.1523/JNEUROSCI.0295-04.2004

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Development/Plasticity/Repair
Survival of Developing Motor Neurons Mediated by Rho GTPase Signaling Pathway through Rho-Kinase

Kenta Kobayashi,¹ Masanori Takahashi,² Natsuki Matsushita,³ Jun-ichi Miyazaki,⁴ Masato Koike,⁵ Hiroyuki Yaginuma,⁵ Noriko Osumi,² Kozo Kaibuchi,⁶ and Kazuto Kobayashi¹

¹Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan, ²Department of Developmental Neurobiology, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan, ³Department of Embryology, Institute for Developmental Research, Aichi Human Service Center, Kasugai 480-0392, Japan, ⁴Division of Stem Cell Regulation Research, Osaka University Graduate School of Medicine, Suita 565-0871, Japan, ⁵Department of Anatomy, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan, and ⁶Department of Cell Pharmacology, Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

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.

Key words: small GTPase signaling; neuronal survival; programmed cell death; apoptosis; axon patterning; motor neuron

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Received July 29, 2003; revised February 20, 2004; accepted February 21, 2004.

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