D40p53 is a transactivation-deficient isoform of the tumor suppressor p53. We discovered that D40p53, in addition to being highly expressed in embryonic stem cells (ESCs), is the major p53 isoform during early stages of embryogenesis in the mouse. By altering the dose of D40p53 in ESCs, we identified a critical role for this isoform in maintaining the ESC state. Haploinsufficiency for D40p53 causes a loss of pluripotency in ESCs and acquisition of a somatic cell cycle, while increased dosage of D40p53 prolongs pluripotency and inhibits progression to a more differentiated state. D40p53 controls the switch from pluripotent ESCs to differentiated somatic cells by controlling the activity of full-length p53 at critical targets such as Nanog and the IGF-1 receptor (IGF-1R). The IGF axis plays a central role in the switch between pluripotency and differentiation in ESCs-and D40p53, by controlling the level of the IGF-1R, acts as a master regulator of this switch. We propose that this is the primary function of D40p53 in cells of the early embryo and stem cells, which are the only normal cells in which this isoform is expressed.[Keywords: D40p53; embryonic stem cells; pluripotency; IGF] Supplemental material is available at http://www.genesdev.org.
Sex determination of the gonad is an extraordinary process by which a single organ anlage is directed to form one of two different structures, a testis or an ovary. Morphogenesis of these two organs utilizes many common cellular events; differences in the timing and execution of these events must combine to generate sexually dimorphic structures. In this chapter, we review recent research on the cellular processes of gonad morphogenesis, focusing on data from mouse models. We highlight the shared cellular mechanisms in testis and ovary morphogenesis and examine the differences that enable formation of the two organs responsible for the perpetuation of all sexually reproducing species.
BackgroundMice exposed to high levels of arsenic in utero have increased susceptibility to tumors such as hepatic and pulmonary carcinomas when they reach adulthood. However, the effects of in utero arsenic exposure on general physiological functions such as reproduction and metabolism remain unclear.ObjectivesWe evaluated the effects of in utero exposure to inorganic arsenic at the U.S. Environmental Protection Agency (EPA) drinking water standard (10 ppb) and at tumor-inducing levels (42.5 ppm) on reproductive end points and metabolic parameters when the exposed females reached adulthood.MethodsPregnant CD-1 mice were exposed to sodium arsenite [none (control), 10 ppb, or 42.5 ppm] in drinking water from gestational day 10 to birth, the window of organ formation. At birth, exposed offspring were fostered to unexposed dams. We examined reproductive end points (age at vaginal opening, reproductive hormone levels, estrous cyclicity, and fertility) and metabolic parameters (body weight changes, hormone levels, body fat content, and glucose tolerance) in the exposed females when they reached adulthood.ResultsArsenic-exposed females (10 ppb and 42.5 ppm) exhibited early onset of vaginal opening. Fertility was not affected when females were exposed to the 10-ppb dose. However, the number of litters per female was decreased in females exposed to 42.5 ppm of arsenic in utero. In both 10-ppb and 42.5-ppm groups, arsenic-exposed females had significantly greater body weight gain, body fat content, and glucose intolerance.ConclusionOur findings revealed unexpected effects of in utero exposure to arsenic: exposure to both a human-relevant low dose and a tumor-inducing level led to early onset of vaginal opening and to obesity in female CD-1 mice.CitationRodriguez KF, Ungewitter EK, Crespo-Mejias Y, Liu C, Nicol B, Kissling GE, Yao HH. 2016. Effects of in utero exposure to arsenic during the second half of gestation on reproductive end points and metabolic parameters in female CD-1 mice. Environ Health Perspect 124:336–343; http://dx.doi.org/10.1289/ehp.1509703
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