SNF5/INI1 is a component of the ATP-dependent chromatin remodeling enzyme family SWI/SNF. Germ line mutations of INI1 have been identified in children with brain and renal rhabdoid tumors, indicating that INI1is a tumor suppressor. Here we report that disruption of Ini1 expression in mice results in early embryonic lethality. Ini1-null embryos die between 3.5 and 5.5 days postcoitum, and Ini1-null blastocysts fail to hatch, form the trophectoderm, or expand the inner cell mass when cultured in vitro. Furthermore, we report that approximately 15% of Ini1-heterozygous mice present with tumors, mostly undifferentiated or poorly differentiated sarcomas. Tumor formation is associated with a loss of heterozygocity at the Ini1 locus, characterizing Ini1 as a tumor suppressor in mice. Thus, Ini1 is essential for embryo viability and for repression of oncogenesis in the adult organism.The compact nature of chromatin structure presents a barrier to cellular processes that require access to DNA. A number of multiprotein complexes have been identified that share the ability to modify chromatin structure. These include the histone acetyltransferases and deacetylases, complexes which chemically modify the amino-terminal tails of histones by the addition or removal of acetyl groups, respectively, as well as a group of enzymes that utilize the energy derived from ATP hydrolysis to alter nucleosome structure (16,20,43,44,50). Included among these ATP-dependent chromatin remodeling enzymes is the SWI/SNF family of chromatin modifiers.SWI/SNF enzymes are large multisubunit enzymes of ϳ1 to 2 MDa. Yeast SWI/SNF genes were originally identified as being required for mating type switching or sucrose fermentation (4,32,42). Later work determined that SWI/SNF genes were required for the induction of a subset of yeast genes and that the SWI2/SNF2 protein possessed a DNA-stimulated ATPase activity (6,22,26,33,34,54). Mutations in SWI/SNF genes could be suppressed by mutations altering histone gene expression, histone structure, or nonhistone chromatin proteins, leading to the suggestion that these gene products facilitated transcriptional activation by altering chromatin structure (15,23,24).Human SWI/SNF (hSWI/SNF) complexes contain either the human BRM (hBRM) (hSNF2␣) or BRG1 (hSNF2␤) homologues of the yeast SWI2/SNF2 ATPase (7,19,30). Both yeast and human SWI/SNF complexes have been shown to possess nucleosome remodeling activity in vitro (8,17,25). Components of mammalian SWI/SNF complexes have been implicated in a variety of cellular processes, including gene activation and repression, development and differentiation, recombination and repair, and cell cycle control. There is evidence supporting a role for SWI/SNF in gene activation events mediated by nuclear hormone receptors, environmental stress, and viral infection (1,7,10,13,30). In contrast, SWI/SNF components also were shown to be involved in repression of c-fos and some E2F-regulated genes (31, 48). Both BRG1 and hBRM can interact with the retinoblastoma oncoprotein and indu...

There is increasing evidence that the oxygen supply to the human embryo in the first trimester is tightly controlled, suggesting that too much oxygen may interfere with development. The use of hypoxia probes in mammalian embryos during the organogenic period indicates that the embryo is normally in a state of partial hypoxia, and this may be essential to control cardiovascular development, perhaps under the control of hypoxia-inducible factor (HIF). A consequence of this state of partial hypoxia is that disturbances in the oxygen supply can more easily lead to a damaging degree of hypoxia. Experimental mammalian embryos show a surprising degree of resilience to hypoxia, with many organogenic stage embryos able to survive 30-60 min of anoxia. However, in some embryos this degree of hypoxia causes abnormal development, particularly transverse limb reduction defects. These abnormalities are preceded by hemorrhage/edema and tissue necrosis. Other parts of the embryo are also susceptible to this hypoxia-induced damage and include the genital tubercle, the developing nose, the tail, and the central nervous system. Other frequently observed defects in animal models of prenatal hypoxia include cleft lip, maxillary hypoplasia, and heart defects. Animal studies indicate that hypoxic episodes in the first trimester of human pregnancy could occur by temporary constriction of the uterine arteries. This could be a consequence of exposure to cocaine, misoprostol, or severe shock, and there is evidence that these exposures have resulted in hypoxia-related malformations in the human. Exposure to drugs that block the potassium current (IKr) can cause severe slowing and arrhythmia of the mammalian embryonic heart and consequently hypoxia in the embryo. These drugs are highly teratogenic in experimental animals. There is evidence that drugs with IKr blockade as a side effect, for example phenytoin, may cause birth defects in the human by causing periods of embryonic hypoxia. The strongest evidence of hypoxia causing birth defects in the human comes from studies of fetuses lacking hemoglobin (Hb) F. These fetuses are thought to be hypoxic from about the middle of the first trimester and show a range of birth defects, particularly transverse limb reduction defects. Birth Defects Research (Part C) 81: [215][216][217][218][219][220][221][222][223][224][225][226][227][228] 2007. V C 2007 Wiley-Liss, Inc.

To investigate the teratogenic effect of acute alcohol exposure, pregnant C57BL/6J mice were exposed to 25% ethanol (either two doses of 2.9g/kg or one dose 5.8g/kg) during the organogenic period either by intraperitoneal injections or by intubation. The incidence of malformations varied according to (1) the stage of embryonic development at the time of exposure, (2) the route of administration of the alcohol, and (3) the amount of alcohol given and the time period over which it was administered. Oral doses of alcohol were teratogenic although less so than the same dose given intraperitoneally, and two intraperitoneal doses four hours apart produced significantly more malformation than the same two doses six hours apart. The primary metabolite of alcohol, acetaldehyde, was also investigated for its teratogenicity. It was found that one or two doses of four percent acetaldehyde (0.32g/kg), administered intraperitoneally were teratogenic. A further attempt was made to raise blood acetaldehyde levels by exposing mice to disulfiram, an inhibitor of acetaldehyde dehydrogenase, prior to administration of alcohol. The disulfiram pretreatment did not increase the malformation rate. Treatment with alcohol on day 7 or 8 caused a variety of facial abnormalities, some of which were comparable to those seen in children with fetal alcohol syndrome. Exposure on day 9 or 10 resulted in limb defects. The results suggest that one or more episodes of heavy maternal drinking at critical periods in pregnancy may severely damage the embryo and may produce many features of the fetal alcohol syndrome.