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Molecular and Cellular Biology, October 2003, p. 7122-7133, Vol. 23, No. 20
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.20.7122-7133.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

PAK4 Kinase Is Essential for Embryonic Viability and for Proper Neuronal Development

Department of Biological Sciences, Columbia University, New York, New York 10025,¹ Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115,³ Howard Hughes Medical Institute, Department of Biochemistry and Molecular Biophysics, Center for Neurobiology and Behavior, Columbia University, New York, New York 10032²

Received 20 March 2003/ Returned for modification 9 May 2003/ Accepted 7 July 2003

The serine/threonine kinase PAK4 is a target for the Rho GTPase Cdc42 and has been shown to regulate cell morphology and cytoskeletal organization in mammalian cells. To examine the physiological and developmental functions of PAK4, we have disrupted the PAK4 gene in mice. The absence of PAK4 led to lethality by embryonic day 11.5, a result most likely due to a defect in the fetal heart. Striking abnormalities were also evident in the nervous systems of PAK4-deficient embryos. These embryos had dramatic defects in neuronal development and axonal outgrowth. In particular, spinal cord motor neurons and interneurons failed to differentiate and migrate to their proper positions. This is probably related to the role for PAK4 in the regulation of cytoskeletal organization and cell and/or extracellular matrix adhesion. PAK4-null embryos also had defects in proper folding of the caudal portion of the neural tube, suggesting an important role for PAK4 in neural tube development.

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