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Female Fertility Is Reduced in Mice Lacking Ca²⁺/Calmodulin-Dependent Protein Kinase IV¹

Department of Pharmacology and Cancer Biology (J.Y.W., A.R.M.), Duke University Medical Center, Durham, North Carolina 27710; Department of Cell Biology (I.J.G.-R., J.S.R.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Anthony R. Means, Ph.D., Duke University Medical Center, Department of Pharmacology, Box 3813, C238 LSRC Lasalle Street, Durham, North Carolina 27710. E-mail: meansool{at}mc.duk.edu

Ca²⁺/calmodulin-dependent protein kinase IV (CaMKIV) is a serine/threonine protein kinase with limited tissue distribution. CaMKIV is highly expressed in the testis, where it is found in transcriptionally inactive elongating spermatids. We have recently generated mice deficient in CaMKIV. In the absence of CaMKIV, the exchange of sperm nuclear basic proteins in male spermatids is impaired, resulting in male infertility secondary to defective spermiogenesis. The involvement of CaMKIV in female fertility has not been addressed. Here we report that female fertility is markedly reduced in CaMKIV-deficient mice due to impaired follicular development and ovulation. CaMKIV is expressed in the ovary, where it is localized in granulosa cells. We further find that in cultured granulosa cells, CaMKIV expression and subcellular localization are hormonally regulated. As granulosa cells differentiate, CaMKIV levels decrease and the kinase translocates from the nucleus into the cytoplasm. Our results demonstrate a critical role for CaMKIV in female reproduction and point to a potential function in granulosa cell differentiation.

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