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Molecular and Cellular Biology, June 2004, p. 4720-4733, Vol. 24, No. 11
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.11.4720-4733.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Disruption of CCTß2 Expression Leads to Gonadal Dysfunction

Suzanne Jackowski,1,2* Jerold E. Rehg,3 Yong-Mei Zhang,1 Jina Wang,1 Karen Miller,1 Pam Jackson,1 and Mohammad A. Karim1,{dagger}

Departments of Infectious Diseases,1 Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee 38105,3 Department of Molecular Sciences, University of Tennessee Health Science Center, Memphis, Tennessee 381632

Received 21 October 2003/ Returned for modification 3 December 2003/ Accepted 7 March 2004

There are two mammalian genes that encode isoforms of CTP:phosphocholine cytidylyltransferase (CCT), a key rate-controlling step in membrane phospholipid biogenesis. Quantitative determination of the CCT transcripts reveals that CCT{alpha} is ubiquitously expressed and is found at the highest levels in the testis and lung, with lower levels in the liver and ovary. CCTß2 is a very minor isoform in most tissues but is significantly expressed in the brain, lung, and gonads. CCTß3 is the third isoform recently discovered in mice and is expressed in the same tissues as CCTß2, with its highest level in testes. We investigated the role(s) of CCTß2 by generating knockout mice. The brains and lungs of mice lacking CCTß2 expression did not exhibit any overt defects. On the other hand, a large percentage of the CCTß2–/– females were sterile and their ovaries exhibited defective ovarian follicle development. The proportion of female CCTß2–/– mice with defective ovaries increased as the animals aged. The rare litters born from CCTß2–/– x CCTß2–/0 matings had the normal number of pups. The abnormal ovarian histopathology was characterized by disorganization of the tissue in young adult mice and absence of follicles and ova in older mice, along with interstitial stromal cell hyperplasia which culminated in the emergence of tubulostromal ovarian tumors by 16 months of age. Grossly defective CCTß2–/– ovaries were associated with high follicle-stimulating (FSH) and luteinizing (LH) hormone levels. Male CCTß2–/0 mice exhibited progressive multifocal testicular degeneration and reduced fertility but had normal FSH and LH levels. Thus, the most notable phenotype of CCTß2 knockout mice was gonad degeneration and reproductive deficiency. The results indicate that although CCTß2 is expressed at very low levels compared to the {alpha}-isoform, loss of CCTß2 expression causes a breakdown in the gonadal response to hormonal stimulation.

* Corresponding author. Mailing address: Protein Science Division, Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794. Phone: (901) 495-3494. Fax: (901) 495-3099. E-mail: suzanne.jackowski{at}stjude.org.

{dagger} Present address: Division of Endocrinology, Department of Medicine, Central Arkansas Veterans Healthcare System and University of Arkansas for Medical Sciences, Little Rock, AR 72205.

Molecular and Cellular Biology, June 2004, p. 4720-4733, Vol. 24, No. 11
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.11.4720-4733.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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