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      Growth retardation and abnormal maternal behavior in mice lacking testicular orphan nuclear receptor 4

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          Abstract

          Testicular orphan nuclear receptor 4 (TR4) is a member of the nuclear receptor superfamily for which a ligand has not yet been found. In vitro data obtained from various cell lines suggest that TR4 functions as a master regulator to modulate many signaling pathways, yet the in vivo physiological roles of TR4 remain unclear. Here, we report the generation of mice lacking TR4 by means of targeted gene disruption (TR4(-/-)). The number of TR4(-/-) pups generated by the mating of TR4(+/-) mice is well under that predicted by the normal Mendelian ratio, and TR4(-/-) mice demonstrate high rates of early postnatal mortality, as well as significant growth retardation. Additionally, TR4(-/-) females show defects in reproduction and maternal behavior, with pups of TR4(-/-) dams dying soon after birth with no indication of milk intake. These results provide in vivo evidence that TR4 plays important roles in growth, embryonic and early postnatal pup survival, female reproductive function, and maternal behavior.

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          Most cited references35

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          The steroid and thyroid hormone receptor superfamily.

          Analyses of steroid receptors are important for understanding molecular details of transcriptional control, as well as providing insight as to how an individual transacting factor contributes to cell identity and function. These studies have led to the identification of a superfamily of regulatory proteins that include receptors for thyroid hormone and the vertebrate morphogen retinoic acid. Although animals employ complex and often distinct ways to control their physiology and development, the discovery of receptor-related molecules in a wide range of species suggests that mechanisms underlying morphogenesis and homeostasis may be more ubiquitous than previously expected.
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            Mice carrying null mutations of the genes encoding insulin-like growth factor I (Igf-1) and type 1 IGF receptor (Igf1r).

            Newborn mice homozygous for a targeted disruption of insulin-like growth factor gene (Igf-1) exhibit a growth deficiency similar in severity to that previously observed in viable Igf-2 null mutants (60% of normal birthweight). Depending on genetic background, some of the Igf-1(-/-) dwarfs die shortly after birth, while others survive and reach adulthood. In contrast, null mutants for the Igf1r gene die invariably at birth of respiratory failure and exhibit a more severe growth deficiency (45% normal size). In addition to generalized organ hypoplasia in Igf1r(-/-) embryos, including the muscles, and developmental delays in ossification, deviations from normalcy were observed in the central nervous system and epidermis. Igf-1(-/-)/Igf1r(-/-) double mutants did not differ in phenotype from Igf1r(-/-) single mutants, while in Igf-2(-)/Igf1r(-/-) and Igf-1(-/-)/Igf-2(-) double mutants, which are phenotypically identical, the dwarfism was further exacerbated (30% normal size). The roles of the IGFs in mouse embryonic development, as revealed from the phenotypic differences between these mutants, are discussed.
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              Role of insulin-like growth factors in embryonic and postnatal growth.

              A developmental analysis of growth kinetics in mouse embryos carrying null mutations of the genes encoding insulin-like growth factor I (IGF-I), IGF-II, and the type 1 IGF receptor (IGF1R), alone or in combination, defined the onset of mutational effects leading to growth deficiency and indicated that between embryonic days 11.0 and 12.5, IGF1R serves only the in vivo mitogenic signaling of IGF-II. From E13.5 onward, IGF1R interacts with both IGF-I and IGF-II, while IGF-II recognizes an additional unknown receptor (XR). In contrast with the embryo proper, placental growth is served exclusively by an IGF-II-XR interaction. Additional genetic data suggested that the type 2IGF/mannose 6-phosphate receptor is an unlikely candidate for XR. Postnatal growth curves indicated that surviving Igf-1(-/-) mutants, which are infertile and exhibit delayed bone development, continue to grow with a retarded rate after birth in comparison with wild-type littermates and become 30% of normal weight as adults.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                October 19 2004
                October 19 2004
                October 11 2004
                October 19 2004
                : 101
                : 42
                : 15058-15063
                Article
                10.1073/pnas.0405700101
                524065
                15477591
                962b83a8-8cb8-4941-b72b-e233134f52bc
                © 2004
                History

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