Mex3c mutation affects lactation through impairing milk ejection in female mice

Abstract Mouse Mex3c encodes RNA-binding proteins of variant length through alternative splicing. Its mutation results in multiple defects including growth retardation, perturbed energy balance, and defective antiviral innate immunity. Here we report that Mex3c mutation affects mammary gland development and lactation in female mice. Pups of Mex3c mutant dams die of starvation soon after birth. Milk contents are present in the alveoli but deficient in the ducts of the mammary glands in mutant mice. Mutant mice do not show prolactin or oxytocin deficiency. They also develop myoepithelial cells in the mammary glands. Mex3c is expressed in the mammary gland epithelium. Our data suggest that functional defects in mammary gland epithelium or myoepithelial cells could cause lactation defects.

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EFFECT OF LOCALLY IMPLANTED OESTROGEN ON THE RESPONSE OF THE RAT'S LACTATING MAMMARY GLAND TO OXYTOCIN

Acta Endocrinologica ◽

10.1530/acta.0.0730700 ◽

1973 ◽

Vol 73 (4) ◽

pp. 700-712 ◽

Cited By ~ 1

Author(s):

J. D. Bruce ◽

X. Cofre ◽

V. D. Ramirez

Keyword(s):

Mammary Gland ◽

Mammary Glands ◽

Myoepithelial Cells ◽

Recording System ◽

Saline Infusion ◽

High Dose ◽

Low Doses ◽

Milk Ejection ◽

Lactating Mammary Gland ◽

Small Rise

ABSTRACT On the day following delivery (day 1 of lactation) one abdominal mammary gland was implanted with oestrogen and the contralateral gland received an empty needle. At 2, 5 or 10 days of lactation the rats were anaesthetized with pentobarbital and the nipples of both abdominal glands were cannulated and their pressures recorded by means of transducers coupled to an amplifier and recording system. The normal mammary glands of 5-day lactating rats responded to very low doses of oxytocin (Syntocinon®, Sandoz) (5× 10−8 mU) with a rhythmic elevation in pressure. However, saline infusion also evoked a small rise in intra-mammary pressure. Earlier (2 days) and later (10 days) in lactation the responses were smaller. Oestrogen decreases significantly the milk ejection response to oxytocin, and the effect was maximal at day 10 of lactation. Histological observations confirmed the diminished reaction of the gland to oxytocin, since the milk was retained in the alveoli of rats bearing a mammary-oestrogen implant. A paradoxical rise in pressure was detected in normal as well as in oestrogen-implanted glands when the lowest dose of oxytocin was injected in lactating rats which had previously received a high dose of oxytocin (50 mU or 500 mU). These results reinforce the hypothesis that oestrogen alters the milk ejection response to oxytocin and that the mechanism is probably related to changes in the contractility of the myoepithelial cells.

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Enhanced synthesis of gelatinase and stromelysin by myoepithelial cells during involution of the rat mammary gland.

Journal of Histochemistry & Cytochemistry ◽

10.1177/40.5.1315355 ◽

1992 ◽

Vol 40 (5) ◽

pp. 697-703 ◽

Cited By ~ 56

Author(s):

S R Dickson ◽

M J Warburton

Keyword(s):

Mammary Gland ◽

Basement Membrane ◽

Gelatin Zymography ◽

Mammary Glands ◽

Myoepithelial Cells ◽

Immunofluorescence Staining ◽

Rat Mammary Gland

During the involution of the mammary gland there is destruction of the basement membrane as the secretory alveolar structures degenerate. Immunofluorescence staining of sections of rat mammary gland with antibodies to 72 KD gelatinase (MMP-2) and stromelysin (MMP-3) revealed increased production of these two proteinases during involution. This increased expression was mostly restricted to myoepithelial cells. Increased expression during involution was also demonstrated by immunoblotting techniques. Gelatin zymography indicated that the predominant metalloproteinase present in involuting rat mammary glands was a 66 KD gelatinase.

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Progesterone receptor membrane component 1 is required for mammary gland development†

Biology of Reproduction ◽

10.1093/biolre/ioaa164 ◽

2020 ◽

Vol 103 (6) ◽

pp. 1249-1259

Author(s):

Globinna Kim ◽

Jong Geol Lee ◽

Seung-A Cheong ◽

Jung-Min Yon ◽

Myeong Sup Lee ◽

...

Keyword(s):

Mammary Gland ◽

Progesterone Receptor ◽

Mammary Gland Development ◽

Target Genes ◽

Hormone Treatment ◽

Mammary Glands ◽

Membrane Component ◽

Independent Manner ◽

Receptor Membrane ◽

Gland Development

Abstract The physiological functions of progesterone (P4) in female reproductive organs including the mammary glands are mediated via the progesterone receptor (PR), but not all P4 functions can be explained by PR-mediated signaling. Progesterone receptor membrane component 1 (PGRMC1), a potential mediator of P4 actions, plays an important role in the ovary and uterus in maintaining female fertility and pregnancy, but its function in mammary glands has not been elucidated. This study investigated the role of PGRMC1 in mouse mammary gland development. Unlike in the uterus, exogenous estrogen (E2) and/or P4 did not alter PGRMC1 expression in the mammary gland, and Pgrmc1-knockout (KO) mice displayed reduced ductal elongation and side branching in response to hormone treatment. During pregnancy, PGRMC1 was expressed within both the luminal and basal epithelium and gradually increased with gestation and decreased rapidly after parturition. Moreover, although lactogenic capacity was normal after parturition, Pgrmc1 KO resulted in defective mammary gland development from puberty until midpregnancy, while the expression of PR and its target genes was not significantly different between wild-type and Pgrmc1-KO mammary gland. These data suggest that PGRMC1 is essential for mammary gland development during puberty and pregnancy in a PR-independent manner.

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Prenatal Exposure to Unconventional Oil and Gas Operation Chemical Mixtures Altered Mammary Gland Development in Adult Female Mice

Endocrinology ◽

10.1210/en.2017-00866 ◽

2018 ◽

Vol 159 (3) ◽

pp. 1277-1289 ◽

Cited By ~ 8

Author(s):

Sarah A Sapouckey ◽

Christopher D Kassotis ◽

Susan C Nagel ◽

Laura N Vandenberg

Keyword(s):

Mammary Gland ◽

Prenatal Exposure ◽

Adult Female ◽

Mammary Gland Development ◽

Oil And Gas ◽

Chemical Mixtures ◽

Female Mice ◽

Unconventional Oil ◽

Unconventional Oil And Gas ◽

Gland Development

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Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands

The Journal of Cell Biology ◽

10.1083/jcb.200212066 ◽

2003 ◽

Vol 161 (3) ◽

pp. 583-592 ◽

Cited By ~ 37

Author(s):

Rui-An Wang ◽

Ratna K. Vadlamudi ◽

Rozita Bagheri-Yarmand ◽

Iwan Beuvink ◽

Nancy E. Hynes ◽

...

Keyword(s):

Mammary Gland ◽

Epithelial Cells ◽

Mammary Gland Development ◽

Mammary Epithelial Cells ◽

Ectopic Expression ◽

Functional Differentiation ◽

Mammary Glands ◽

Pregnancy And Lactation ◽

P21 Activated Kinase ◽

Gland Development

Although growth factors have been shown to influence mammary gland development, the nature of downstream effectors remains elusive. In this study, we show that the expression of p21-activated kinase (Pak)1, a serine/threonine protein kinase, is activated in mammary glands during pregnancy and lactation. By targeting an ectopic expression of a kinase-dead Pak1 mutant under the control of ovine β-lactoglobulin promoter, we found that the mammary glands of female mice expressing kinase-dead Pak1 transgene revealed incomplete lobuloalveolar development and impaired functional differentiation. The expression of whey acidic protein and β-casein and the amount of activated Stat5 in the nuclei of epithelial cells in transgenic mice were drastically reduced. Further analysis of the underlying mechanisms revealed that Pak1 stimulated β-casein promoter activity in normal mouse mammary epithelial cells and also cooperated with Stat5a. Pak1 directly interacted with and phosphorylated Stat5a at Ser 779, and both COOH-terminal deletion containing Ser 779 of Stat5a and the Ser 779 to Ala mutation completely prevented the ability of Pak1 to stimulate β-casein promoter. Mammary glands expressing inactive Pak1 exhibited a reduction of Stat5a Ser 779 phosphorylation. These findings suggest that Pak1 is required for alveolar morphogenesis and lactation function, and thus, identify novel functions of Pak1 in the mammary gland development.

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Signal Transducer and Activator of Transcription 5a Mediates Mammary Ductal Branching and Proliferation in the Nulliparous Mouse

Endocrinology ◽

10.1210/en.2009-1282 ◽

2010 ◽

Vol 151 (6) ◽

pp. 2876-2885 ◽

Cited By ~ 25

Author(s):

Sarah J. Santos ◽

Sandra Z. Haslam ◽

Susan E. Conrad

Keyword(s):

Mammary Gland ◽

Epithelial Cells ◽

Mammary Gland Development ◽

Kinase Inhibitor ◽

Mammary Epithelial Cells ◽

Nuclear Factor Κb ◽

Mammary Glands ◽

Mammary Epithelial ◽

Signal Transducer ◽

Gland Development

Signal transducer and activator of transcription (Stat)5a is a critical regulator of mammary gland development. Previous studies have focused on Stat5a’s role in the late pregnant and lactating gland, and although active Stat5a is detectable in mammary epithelial cells in virgin mice, little is known about its role during early mammary gland development. In this report, we compare mammary gland morphology in pubertal and adult nulliparous wild-type and Stat5a−/− mice. The Stat5a-null mammary glands exhibited defects in secondary and side branching, providing evidence that Stat5a regulates these processes. In addition, Stat5a−/− mammary glands displayed an attenuated proliferative response to pregnancy levels of estrogen plus progesterone (E+P), suggesting that it plays an important role in early pregnancy. Finally, we examined one potential mediator of Stat5a’s effects, receptor activator of nuclear factor-κB ligand (RANKL). Stat5a−/− mammary glands were defective in inducing RANKL in response to E+P treatment. In addition, regulation of several reported RANKL targets, including inhibitor of DNA binding 2 (Id2), cyclin D1, and the cyclin-dependent kinase inhibitor p21Waf1/Cip1, was altered in Stat5a−/− mammary cells, suggesting that one or more of these proteins mediate the effects of Stat5a in E+P-treated mammary epithelial cells.

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Preeclampsia-Like Features and Partial Lactation Failure in Mice Lacking Cystathionine γ-Lyase—An Animal Model of Cystathioninuria

International Journal of Molecular Sciences ◽

10.3390/ijms20143507 ◽

2019 ◽

Vol 20 (14) ◽

pp. 3507 ◽

Cited By ~ 4

Author(s):

Noriyuki Akahoshi ◽

Hiroki Handa ◽

Rintaro Takemoto ◽

Shotaro Kamata ◽

Masahide Yoshida ◽

...

Keyword(s):

Late Pregnancy ◽

Mammary Glands ◽

Myoepithelial Cells ◽

Receptor Expression ◽

Wild Type ◽

Normal Numbers ◽

Milk Ejection ◽

Blood Pressure Elevation ◽

Pregnant Mice ◽

Milk Ejection Reflex

Elevated plasma homocysteine levels are considered as a risk factor for cardiovascular diseases as well as preeclampsia—a pregnancy disorder characterized by hypertension and proteinuria. We previously generated mice lacking cystathionine γ-lyase (Cth) as cystathioninuria models and found them to be with cystathioninemia/homocysteinemia. We investigated whether Cth-deficient (Cth−/−) pregnant mice display any features of preeclampsia. Cth−/− females developed normally but showed mild hypertension (~10 mmHg systolic blood pressure elevation) in late pregnancy and mild proteinuria throughout development/pregnancy. Cth−/− dams had normal numbers of pups and exhibited normal maternal behavior except slightly lower breastfeeding activity. However, half of them could not raise their pups owing to defective lactation; they could produce/store the first milk in their mammary glands but not often provide milk to their pups after the first ejection. The serum oxytocin levels and oxytocin receptor expression in the mammary glands were comparable between wild-type and Cth−/− dams, but the contraction responses of mammary gland myoepithelial cells to oxytocin were significantly lower in Cth−/− dams. The contraction responses to oxytocin were lower in uteruses isolated from Cth−/− mice. Our results suggest that elevated homocysteine or other unknown factors in preeclampsia-like Cth−/− dams interfere with oxytocin that regulates milk ejection reflex.

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