title: Dual roles for Id4 in the regulation of estrogen signaling in the mammary gland and ovary.
abstract: The HLH transcriptional regulator Id4 exerts important roles in different organs, including the neural compartment, where Id4 loss usually results in early lethality. To explore the role of this basally restricted transcription factor in the mammary gland, we generated a cre-inducible mouse model. MMTV- or K14-cre-mediated deletion of Id4 led to a delay in ductal morphogenesis, consistent with previous findings using a germ-line knockout mouse model. A striking increase in the expression of ERα (Esr1), PR and FoxA1 was observed in both the basal and luminal cellular subsets of Id4-deficient mammary glands. Together with chromatin immunoprecipitation of Id4 on the Esr1 and Foxa1 promoter regions, these data imply that Id4 is a negative regulator of the ERα signaling axis. Unexpectedly, examination of the ovaries of targeted mice revealed significantly increased numbers of secondary and antral follicles, and reduced Id4 expression in the granulosa cells. Moreover, expression of the cascade of enzymes that are crucial for estrogen biosynthesis in the ovary was decreased in Id4-deficient females and uterine weights were considerably lower, indicating impaired estrogen production. Thus, compromised ovarian function and decreased circulating estrogen likely contribute to the mammary ductal defects evident in Id4-deficient mice. Collectively, these data identify Id4 as a novel regulator of estrogen signaling, where Id4 restrains ERα expression in the basal and luminal cellular compartments of the mammary gland and regulates estrogen biosynthesis in the ovary.
authors.affiliation: ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Best
authors.affiliation: Ovarian Biology Laboratory, Prince Henry's Institute, Monash Medical Center, Clayton, Victoria 3168, Australia Department of Anatomy and Developmental Biology, Monash University, Clayton, Victoria 3168, Australia.
authors.forename: Karla J
authors.initials: KJ
authors.lastname: Hutt
authors.affiliation: ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: Nai Yang
authors.initials: NY
authors.lastname: Fu
authors.affiliation: ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia.
authors.forename: François
authors.initials: F
authors.lastname: Vaillant
authors.affiliation: Ovarian Biology Laboratory, Prince Henry's Institute, Monash Medical Center, Clayton, Victoria 3168, Australia.
authors.forename: Seng H
authors.initials: SH
authors.lastname: Liew
authors.affiliation: ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
authors.forename: Lynne
authors.initials: L
authors.lastname: Hartley
authors.affiliation: ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medicine, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Clare L
authors.initials: CL
authors.lastname: Scott
authors.affiliation: ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medicine, The University of Melbourne, Parkville, Victoria 3010, Australia Department of Medical Oncology, The Royal Melbourne Hospital, Parkville, Victoria 3050, Australia.
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.affiliation: ACRF Stem Cells and Cancer Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3010, Australia visvader@wehi.edu.au.
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
mesh_terms: D000818:Animals; D001483:Base Sequence; D047628:Estrogen Receptor alpha / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006107:Granulosa Cells / Q000166:cytology; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000378:metabolism; D051796:Inhibitor of Differentiation Proteins / Q000235:genetics* / Q000502:physiology*; D008321:Mammary Glands, Animal / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010053:Ovary / Q000502:physiology*; D011401:Promoter Regions, Genetic; D011980:Receptors, Progesterone / Q000378:metabolism; D015398:Signal Transduction; D014599:Uterus / Q000502:physiology
chemical_list: D047628:Estrogen Receptor alpha; D004967:Estrogens; C496500:Foxa1 protein, mouse; D051541:Hepatocyte Nuclear Factor 3-alpha; C086479:Idb4 protein, mouse; D051796:Inhibitor of Differentiation Proteins; D011980:Receptors, Progesterone
keywords: Estrogen; ID proteins; Mammary gland; Mouse; Ovary