Paternal RLIM/Rnf12 Is a Survival Factor for Milk-Producing Alveolar Cells

Jiao, Baowei; Ma, Hong; Shokhirev, Maxim N.; Drung, Alexander; Yang, Qin; Shin, Jongdae; Lu, Shaolei; Byron, Meg; Kalantry, Sundeep; Mercurio, Arthur M.; Lawrence, Jeanne B.; Hoffmann, Alexander; Bach, Ingolf

doi:10.1016/j.cell.2012.02.056

Cited by 29 publications

(46 citation statements)

References 45 publications

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“…1B). MMTV-Cre is also expressed in the embryonic epidermis (Jiao et al, 2012) and, as expected, itgb4 -deleted tissue exhibited a loss of β4 staining in the skin (Fig. 1B).…”

Section: Resultssupporting

confidence: 78%

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Sun

Feltri³

et al. 2015

Developmental Biology

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The integrin α6β4 (referred to as β4) is expressed in epithelial cells where it functions as a laminin receptor. Although in vitro studies have implicated β4 in the biology of mammary epithelial cells, its contribution to mammary gland development has not been settled. To address this problem, we generated and analyzed itgb4flox/flox MMTV-Cre− and itgb4flox/flox MMTV-Cre+ mice. The salient features of embryonic mammary tissue from itgb4flox/flox MMTV-Cre+ mice were significantly smaller mammary buds and increased apoptosis in the surrounding mesenchyme. Also, compared to control glands, the itgb4-deleted mammary buds lacked expression of the progenitor cell marker CK14 and they were unable to generate mammary glands upon transplantation into cleared fat pads of recipient mice. Analysis of mammary glands at puberty and during pregnancy revealed that itgb4-diminished mammary tissue was unable to elongate and undergo branching morphogenesis. Micro-dissection of epithelial cells in the mammary bud and of the surrounding mesenchyme revealed that loss of β4 resulted in a significant decrease in the expression of parathyroid hormone related protein (PTHrP) in epithelial cells and of target genes of the PTHrP receptor in mesenchymal cells. Given that the phenotype of the itgb4-deleted mammary tissue mimicked that of the PTHrP knockout, we hypothesized that β4 contributes to mammary gland development by sustaining PTHrP expression and enabling PTHrP signaling. Indeed, the inability of itgb4-deleted mammary buds to elongate was rescued by exogenous PTHrP. These data implicate a critical role for the β4 integrin in mammary gland development and provide a mechanism for this role.

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“…1B). MMTV-Cre is also expressed in the embryonic epidermis (Jiao et al, 2012) and, as expected, itgb4 -deleted tissue exhibited a loss of β4 staining in the skin (Fig. 1B).…”

Section: Resultssupporting

confidence: 78%

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Sun

Feltri³

et al. 2015

Developmental Biology

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“…In mouse mammary epithelial cells, X-chromosome inactivation is not random but is preferentially maternally inactivated (Jiao et al, 2012). Interestingly, the X-linked gene ring finger protein 12 (Rnf12), which encodes the ubiquitin ligase Rnf12/RLIM, is a critical survival factor for milk-producing alveolar cells (Jiao et al, 2012).…”

Section: Imprinting In the Mammary Glandmentioning

confidence: 99%

“…Interestingly, the X-linked gene ring finger protein 12 (Rnf12), which encodes the ubiquitin ligase Rnf12/RLIM, is a critical survival factor for milk-producing alveolar cells (Jiao et al, 2012). In humans, limited studies of gene expression in the breast have similarly demonstrated monoallelic expression of growth and survival factors in normal breast tissues.…”

Section: Imprinting In the Mammary Glandmentioning

confidence: 99%

Post-natal imprinting: evidence from marsupials

et al. 2014

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Genomic imprinting has been identified in therian (eutherian and marsupial) mammals but not in prototherian (monotreme) mammals. Imprinting has an important role in optimising pre-natal nutrition and growth, and most imprinted genes are expressed and imprinted in the placenta and developing fetus. In marsupials, however, the placental attachment is short-lived, and most growth and development occurs post-natally, supported by a changing milk composition tailor-made for each stage of development. Therefore there is a much greater demand on marsupial females during post-natal lactation than during pre-natal placentation, so there may be greater selection for genomic imprinting in the mammary gland than in the short-lived placenta. Recent studies in the tammar wallaby confirm the presence of genomic imprinting in nutrient-regulatory genes in the adult mammary gland. This suggests that imprinting may influence infant post-natal growth via the mammary gland as it does pre-natally via the placenta. Similarly, an increasing number of imprinted genes have been implicated in regulating feeding and nurturing behaviour in both the adult and the developing neonate/offspring in mice. Together these studies provide evidence that genomic imprinting is critical for regulating growth and subsequently the survival of offspring not only pre-natally but also post-natally.

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“…In mouse mammary epithelial cells the maternal X chromosome is non-randomly silenced (Jiao et al, 2012). In humans monoallelic expression of Igf2 by mammary epithelium is the norm (Yun et al, 1999).…”

Section: Lactationmentioning

confidence: 99%

Maternal regulation of offspring development in mammals is an ancient adaptation tied to lactation

Power

Schulkin

2013

Applied & Translational Genomics

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The developmental origins of health and disease (DOHaD) is a paradigm for understanding metabolic diseases of modern humans. Vulnerability to disease is linked to perturbations in development during critical time periods in fetal and neonatal life. These perturbations are caused by environmental signals, often generated or transduced by the mother. The regulation of mammalian development depends to a large extent on maternal biochemical signals to her offspring. We argue that this adaptation is ancient, and originated with the evolution of lactation. Lactation evolved earlier than live birth and before the extensive placental development of modern eutherian mammals. Milk contains a host of signaling molecules including nutrients, immunoglobulins, growth factors and metabolic hormones. As evidenced by marsupials, lactation originally served to supply the biochemical factors for growth and development for what is essentially a fetus to a weanling transitioning to independent existence. In placental mammals maternal signaling in earliest life is accomplished through the maternal–placental–fetal connection, with more of development shifted to in utero life. However, significant development occurs postpartum, supported by milk. Mothers of all taxa provide biochemical signals to their offspring, but for non-mammalian mothers the time window is short. Developing mammals receive maternal biochemical signals over an extended period. These signals serve to guide normal development, but also can vary in response to environmental conditions. The ancient adaptation of lactation resulted in a lineage (mammals) in which maternal regulation of offspring development evolved to a heightened degree, with the ability to modify development at multiple time points. Modern metabolic diseases may arise due to a mismatch between maternal regulation and eventual circumstances of the offspring, and due to a large proportion of mothers that exceed past evolutionary norms in body fat and pregnancy weight gain such that maternal signals may no longer be within the adaptive range.

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Paternal RLIM/Rnf12 Is a Survival Factor for Milk-Producing Alveolar Cells

Cited by 29 publications

References 45 publications

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Integrin β4 regulation of PTHrP underlies its contribution to mammary gland development

Post-natal imprinting: evidence from marsupials

Maternal regulation of offspring development in mammals is an ancient adaptation tied to lactation

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