Pituitary hypoplasia and lactotroph dysfunction in mice deficient for cyclin-dependent kinase-4.
The lactotroph undergoes dynamic regulation of cell cycle progression during pregnancy, as well as throughout the development of the pituitary. We recently reported that female mice with targeted disruption of Cdk4, one of the G(1)-regulatory cyclin-dependent kinases, are unable to support embryo implantation because of defective progesterone secretion from the corpus luteum. In this study, we demonstrate that this phenotype is not attributable to a primary defect in the corpus luteum but is a consequence of defective prolactin (PRL) production caused by inappropriate development of the pituitary lactotroph population. Specifically, the pituitary of Cdk4-deficient mice is extremely hypoplastic. Lactotrophs and somatotrophs of prepubertal Cdk4-deficient mice were 80% decreased in number, relative to those in wild-type mice, whereas gonadotrophs were unaffected. Lactotrophs of Cdk4-deficient mice did not proliferate in response to estrogen administration, whereas estrogen could induce the expression of galanin, an estrogen-responsive factor required for lactotroph proliferation. The reduction in lactotroph numbers was reflected by markedly diminished serum PRL levels in both prepubertal and postcoital Cdk4-deficient mice. Administration of PRL, after mating, significantly increased serum progesterone levels and restored implantation in Cdk4-deficient female mice. These observations demonstrate that Cdk4 is required for normal proliferation of the lactotroph population.
Department of Molecular Genetics, University of Illinois College of Medicine, 900 S Ashland Avenue, Chicago, IL 60607-7170, USA.
David S
DS
Moons
Siwanon
S
Jirawatnotai
A F
AF
Parlow
Geula
G
Gibori
Rhonda D
RD
Kineman
Hiroaki
H
Kiyokawa
D000818:Animals; D002455:Cell Division; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D013006:Growth Hormone / Q000378:metabolism; D007247:Infertility, Female / Q000209:etiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010902:Pituitary Gland / Q000378:metabolism / Q000473:pathology*; D011388:Prolactin / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics
D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases; D004268:DNA-Binding Proteins; D013006:Growth Hormone; D011388:Prolactin; D011518:Proto-Oncogene Proteins; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; C494185:Pou1f1 protein, mouse; C495902:Cdk4 protein, mouse