+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Generation of mice expressing only the long form of the prolactin receptor reveals that both isoforms of the receptor are required for normal ovarian function



Generation of mice expressing only the long form of the prolactin receptor reveals that both isoforms of the receptor are required for normal ovarian function



Biology of Reproduction 86(3): 86



Prolactin (PRL), a pleiotropic hormone essential for maintenance of corpus luteum (CL) function and pregnancy, transduces its signal through two types of receptors, a short form (PRLR-S) and a long form (PRLR-L). Both types of receptors are expressed in the CL, yet their individual roles are not well defined. We have shown previously that female transgenic mice expressing only PRLR-S display total infertility characterized by defective follicular development and early degeneration of CL, suggesting that expression of PRLR-L is a prerequisite for normal follicular development and maintenance of CL. To determine whether PRLR-L alone is the sole receptor required to maintain normal CL formation, differentiation, and progesterone secretion, we generated two transgenic mice which express only PRLR-L, either ubiquitously (Tg-RL) or in a CL-specific manner (CL-RL). To generate CL-specific expression, we used the HSD17B7 promoter. We found both transgenic mice models cycled normally, displayed no apparent defect in follicular development, and had normal ovulation rates. The STAT5 signaling pathway, considered essential for luteinization and progesterone production, was activated by PRL in both transgenic mice models. However, soon after mating, Tg-RL and CL-RL mice showed early regression of CL, lack of progesterone production, and implantation failure that rendered them totally infertile. Embryo transfer studies demonstrated no embryo abnormalities, and supplementation with progesterone rescued implantation failure in these mice. Close observation revealed lack of luteinization and reduced expression of proteins involved in progesterone biosynthesis despite normal levels of LHCGR (LH-R), ESR1 (ER-alpha), CEBPB (C/EBP-beta) and CDKN1B (p27), proteins essential for luteinization. However, we found VEGFA, a key regulator of angiogenesis and vascularization, to be dramatically reduced in both Tg-RL and CL-RL mice. We also found collagen IV, a marker for the basal lamina of endothelial cells, aberrantly expressed and a discordant organization of endothelial cells in CL. Although luteinization did not occur in vivo, granulosa cells isolated from these mice luteinized in culture. Taken together, these results suggest that a vascularization defect in the CL may be responsible for lack of luteinization, progesterone production, and infertility in mice expressing only PRLR-L. This investigation therefore demonstrates that in contrast to earlier presumptions that PRLR-L alone is able to support normal CL formation and function, both isoforms of the PRL receptor are required in the CL for normal female fertility.

Please choose payment method:






(PDF emailed within 0-6 h: $19.90)

Accession: 036367034

Download citation: RISBibTeXText

PMID: 22190699

DOI: 10.1095/biolreprod.111.095927


Related references

Intramolecular disulfide bonds of the prolactin receptor short form are required for its inhibitory action on the function of the long form of the receptor. Molecular and Cellular Biology 29(10): 2546-2555, 2009

Prolactin activation of the long form of its cognate receptor causes increased visceral fat and obesity in males as shown in transgenic mice expressing only this receptor subtype. Hormone and Metabolic Research 43(13): 931-937, 2012

Impact of subdomain D1 of the short form S1b of the human prolactin receptor on its inhibitory action on the function of the long form of the receptor induced by prolactin. Biochimica et Biophysica Acta 1840(7): 2272-2280, 2014

Mouse prolactin receptor gene: genomic organization reveals alternative promoter usage and generation of isoforms via alternative 3'-exon splicing. Dna and Cell Biology 17(9): 761-770, 1998

Sequence and functional characterisation of the marmoset monkey (Callithrix jacchus) prolactin receptor: Comparative homology with the human long-form prolactin receptor. Molecular and Cellular Endocrinology 167(1-2): 89-97, 2000

Mice expressing a mutant form of the alpha4 nicotinic receptor subunit show altered function as measured by nicotinic acetylcholine receptor-stimulated -GABA release. Society for Neuroscience Abstract Viewer & Itinerary Planner : Abstract No 248 3, 2003

Human prolactin receptor variants in breast cancer: low ratio of short forms to the long-form human prolactin receptor associated with mammary carcinoma. Cancer Research 64(16): 5677-5682, 2004

Stress-induced analgesia in mu-opioid receptor knockout mice reveals normal function of the delta-opioid receptor system. Brain Research 869(1-2): 1-5, 2000

Analysis of rainbow trout Ah receptor protein isoforms in cell culture reveals conservation of function in Ah receptor-mediated signal transduction. Biochemical Pharmacology 64(1): 49-60, 1 July, 2002

A short form of the prolactin (PRL) receptor is able to rescue mammopoiesis in heterozygous PRL receptor mice. Molecular Endocrinology 17(6): 1066-1074, 2003

Murine tumor cells expressing the gene for the human interferon alpha beta receptor elicit antibodies in syngeneic mice to the active form of the receptor. European Journal of Immunology 21(2): 447-451, 1991

Mutational dissection of the Drosophila ecdysone receptor gene EcR is required maternally for normal oogenesis and EcR-B isoforms are required for neuronal remodeling during metamorphosis. Developmental Biology 198(1): 221, 1998

Downregulation of long-form prolactin receptor mRNA during prolactin-induced luteal regression. European Journal of Endocrinology 143(2): 285-292, 2000