Circadian Clock mutation disrupts estrous cyclicity and maintenance of pregnancy

Brooke H. Miller, Susan Losee Olson, Fred W. Turek, Jon E. Levine, Teresa H. Horton, Joseph S. Takahashi

Research output: Contribution to journalArticle

227 Citations (Scopus)

Abstract

Classic experiments have shown that ovulation and estrous cyclicity are under circadian control and that surgical ablation of the suprachiasmatic nuclei (SCN) results in estrous acyclicity in rats [1-3]. Here, we characterized reproductive function in the circadian Clock mutant mouse [4, 5] and found that the circadian Clock mutation both disrupts estrous cyclicity and interferes with the maintenance of pregnancy. Clock mutant females have extended, irregular estrous cycles, lack a coordinated luteinizing hormone (LH) surge on the day of proestrus, exhibit increased fetal reabsorption during pregnancy, and have a high rate of full-term pregnancy failure. Clock mutants also show an unexpected decline in progesterone levels at midpregnancy and a shortened duration of pseudopregnancy, suggesting that maternal prolactin release may be abnormal. In a second set of experiments, we interrogated the function of each level of the hypothalamic-pituitary-gonadal (HPG) axis in order to determine how the Clock mutation disrupts estrous cyclicity. We report that Clock mutants fail to show an LH surge following estradiol priming in spite of the fact that hypothalamic levels of gonadotropin-releasing hormone (GnRH), pituitary release of LH, and serum levels of estradiol and progesterone are all normal in Clock/Clock females. These data suggest that Clock mutants lack an appropriate circadian daily-timing signal required to coordinate hypothalamic hormone secretion. Defining the mechanisms by which the Clock mutation disrupts reproductive function offers a model for understanding how circadian genes affect complex physiological systems.

Original languageEnglish (US)
Pages (from-to)1367-1373
Number of pages7
JournalCurrent Biology
Volume14
Issue number15
DOIs
StatePublished - Aug 10 2004

Fingerprint

Pregnancy Maintenance
Circadian Clocks
Periodicity
Luteinizing Hormone
periodicity
circadian rhythm
Clocks
pregnancy
mutation
luteinizing hormone
mutants
Mutation
Progesterone
Estradiol
Pseudopregnancy
Hypothalamic Hormones
Proestrus
Pregnancy
Suprachiasmatic Nucleus
Estrous Cycle

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)

Cite this

Circadian Clock mutation disrupts estrous cyclicity and maintenance of pregnancy. / Miller, Brooke H.; Olson, Susan Losee; Turek, Fred W.; Levine, Jon E.; Horton, Teresa H.; Takahashi, Joseph S.

In: Current Biology, Vol. 14, No. 15, 10.08.2004, p. 1367-1373.

Research output: Contribution to journalArticle

Miller, Brooke H. ; Olson, Susan Losee ; Turek, Fred W. ; Levine, Jon E. ; Horton, Teresa H. ; Takahashi, Joseph S. / Circadian Clock mutation disrupts estrous cyclicity and maintenance of pregnancy. In: Current Biology. 2004 ; Vol. 14, No. 15. pp. 1367-1373.
@article{aca09e7235944ac8a2d92707798b5670,
title = "Circadian Clock mutation disrupts estrous cyclicity and maintenance of pregnancy",
abstract = "Classic experiments have shown that ovulation and estrous cyclicity are under circadian control and that surgical ablation of the suprachiasmatic nuclei (SCN) results in estrous acyclicity in rats [1-3]. Here, we characterized reproductive function in the circadian Clock mutant mouse [4, 5] and found that the circadian Clock mutation both disrupts estrous cyclicity and interferes with the maintenance of pregnancy. Clock mutant females have extended, irregular estrous cycles, lack a coordinated luteinizing hormone (LH) surge on the day of proestrus, exhibit increased fetal reabsorption during pregnancy, and have a high rate of full-term pregnancy failure. Clock mutants also show an unexpected decline in progesterone levels at midpregnancy and a shortened duration of pseudopregnancy, suggesting that maternal prolactin release may be abnormal. In a second set of experiments, we interrogated the function of each level of the hypothalamic-pituitary-gonadal (HPG) axis in order to determine how the Clock mutation disrupts estrous cyclicity. We report that Clock mutants fail to show an LH surge following estradiol priming in spite of the fact that hypothalamic levels of gonadotropin-releasing hormone (GnRH), pituitary release of LH, and serum levels of estradiol and progesterone are all normal in Clock/Clock females. These data suggest that Clock mutants lack an appropriate circadian daily-timing signal required to coordinate hypothalamic hormone secretion. Defining the mechanisms by which the Clock mutation disrupts reproductive function offers a model for understanding how circadian genes affect complex physiological systems.",
author = "Miller, {Brooke H.} and Olson, {Susan Losee} and Turek, {Fred W.} and Levine, {Jon E.} and Horton, {Teresa H.} and Takahashi, {Joseph S.}",
year = "2004",
month = "8",
day = "10",
doi = "10.1016/j.cub.2004.07.055",
language = "English (US)",
volume = "14",
pages = "1367--1373",
journal = "Current Biology",
issn = "0960-9822",
publisher = "Cell Press",
number = "15",

}

TY - JOUR

T1 - Circadian Clock mutation disrupts estrous cyclicity and maintenance of pregnancy

AU - Miller, Brooke H.

AU - Olson, Susan Losee

AU - Turek, Fred W.

AU - Levine, Jon E.

AU - Horton, Teresa H.

AU - Takahashi, Joseph S.

PY - 2004/8/10

Y1 - 2004/8/10

N2 - Classic experiments have shown that ovulation and estrous cyclicity are under circadian control and that surgical ablation of the suprachiasmatic nuclei (SCN) results in estrous acyclicity in rats [1-3]. Here, we characterized reproductive function in the circadian Clock mutant mouse [4, 5] and found that the circadian Clock mutation both disrupts estrous cyclicity and interferes with the maintenance of pregnancy. Clock mutant females have extended, irregular estrous cycles, lack a coordinated luteinizing hormone (LH) surge on the day of proestrus, exhibit increased fetal reabsorption during pregnancy, and have a high rate of full-term pregnancy failure. Clock mutants also show an unexpected decline in progesterone levels at midpregnancy and a shortened duration of pseudopregnancy, suggesting that maternal prolactin release may be abnormal. In a second set of experiments, we interrogated the function of each level of the hypothalamic-pituitary-gonadal (HPG) axis in order to determine how the Clock mutation disrupts estrous cyclicity. We report that Clock mutants fail to show an LH surge following estradiol priming in spite of the fact that hypothalamic levels of gonadotropin-releasing hormone (GnRH), pituitary release of LH, and serum levels of estradiol and progesterone are all normal in Clock/Clock females. These data suggest that Clock mutants lack an appropriate circadian daily-timing signal required to coordinate hypothalamic hormone secretion. Defining the mechanisms by which the Clock mutation disrupts reproductive function offers a model for understanding how circadian genes affect complex physiological systems.

AB - Classic experiments have shown that ovulation and estrous cyclicity are under circadian control and that surgical ablation of the suprachiasmatic nuclei (SCN) results in estrous acyclicity in rats [1-3]. Here, we characterized reproductive function in the circadian Clock mutant mouse [4, 5] and found that the circadian Clock mutation both disrupts estrous cyclicity and interferes with the maintenance of pregnancy. Clock mutant females have extended, irregular estrous cycles, lack a coordinated luteinizing hormone (LH) surge on the day of proestrus, exhibit increased fetal reabsorption during pregnancy, and have a high rate of full-term pregnancy failure. Clock mutants also show an unexpected decline in progesterone levels at midpregnancy and a shortened duration of pseudopregnancy, suggesting that maternal prolactin release may be abnormal. In a second set of experiments, we interrogated the function of each level of the hypothalamic-pituitary-gonadal (HPG) axis in order to determine how the Clock mutation disrupts estrous cyclicity. We report that Clock mutants fail to show an LH surge following estradiol priming in spite of the fact that hypothalamic levels of gonadotropin-releasing hormone (GnRH), pituitary release of LH, and serum levels of estradiol and progesterone are all normal in Clock/Clock females. These data suggest that Clock mutants lack an appropriate circadian daily-timing signal required to coordinate hypothalamic hormone secretion. Defining the mechanisms by which the Clock mutation disrupts reproductive function offers a model for understanding how circadian genes affect complex physiological systems.

UR - http://www.scopus.com/inward/record.url?scp=4143150775&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4143150775&partnerID=8YFLogxK

U2 - 10.1016/j.cub.2004.07.055

DO - 10.1016/j.cub.2004.07.055

M3 - Article

VL - 14

SP - 1367

EP - 1373

JO - Current Biology

JF - Current Biology

SN - 0960-9822

IS - 15

ER -