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Role for p21-activated kinase PAK4 in development of the mammalian heart

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Abstract

The serine-threonine kinase PAK4 plays a pivotal role in cell proliferation, survival, and control of the cytoskeleton. Mice that lack Pak4 die in midgestation prior to embryonic day E11 from unidentified causes. Analysis of PAK4 protein levels demonstrated that it was highly expressed in the whole embryo and in the developing heart but became low in the hearts of adult mice. In this study we analyzed development of the heart in conventional and conditional Pak4 knockout mice and embryos. We found that in conventional Pak4 knockout mice cardiogenesis is strongly affected from early developmental stages and by E9.5, hearts of Pak4 −/− embryos developed multiple profound deficits. Conditional deletion of Pak4 in the progenitors of the secondary heart field led to abnormal development of the outflow tract, in which the pulmonary artery had a smaller diameter, and the aortal wall was thinner than in wildtype mice. The conditional knockout mice also displayed the characteristic enlargement of the right ventricles and right atria. Pak4 −/− embryos and cardiomyocytes in which PAK4 was depleted exhibited low levels of LIMK1, a protein that plays key roles in cytoskeletal organization. Knock down of PAK4 in cultured cardiomyocytes led to severely compromised sarcomeric structure and deficits in contraction. These results indicate that PAK4 functions, including control of actin dynamics, are necessary for normal development of the heart.

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Acknowledgments

We thank Dr. Sylvia Evans for generously providing us with Isl1 Cre/+ mice created in her laboratory and John Shelton for valuable suggestions related to heart histology. We are grateful to Michal Sheleg and Alexander Son for their help. The work was supported by NIH grant R01 CA076342-06 to Audrey Minden.

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  1. Susan Lehman Cullman Laboratory for Cancer Research, Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, 164 Frelinghuysen Road, Piscataway, NJ, 08854, USA

    Tanya Nekrasova & Audrey Minden

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  1. Tanya Nekrasova
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Correspondence to Audrey Minden.

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Nekrasova, T., Minden, A. Role for p21-activated kinase PAK4 in development of the mammalian heart. Transgenic Res 21, 797–811 (2012). https://doi.org/10.1007/s11248-011-9578-7

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