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

Abstract

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.

ACKNOWLEDGMENTS

We thank members of A. A. Beg's lab and L. Yamasaki's lab and L. Yamasaki for advice and assistance with the generation of the PAK4 knockout mice. We thank D. Kelley, J. Kitajewski, and T. Jessell for helpful discussions. We thank C. Yang and R. Peraza at the Rockefeller animal facility for help in generation of the knockout mice and Radma Mahmood and Robert Russell for help in analyzing PAK4-null embryos.

This work was supported by a grant from the NIH (CA76342) and an American Scientist Development Grant Award from American Heart Association to A.M. and a grant from the NIH (CA074892) to A.A.B.